Synthesis and structure-activity relationship of a novel class of 15-membered macrolide antibiotics known as '11a-azalides'

Article abstract of DOI:10.1016/j.bmc.2012.08.007

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as '11a-azalides', with substituents at the C12, C13, or C4″ positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4″ substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae.

Full text of DOI:10.1016/j.bmc.2012.08.007

Bioorganic & Medicinal Chemistry 20 (2012) 5787–5801
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and structure–activity relationship of a novel class of 15-membered
macrolide antibiotics known as ‘11a-azalides’
⇑
Tomohiro Sugimoto , Tetsuya Tanikawa, Keiko Suzuki, Yukiko Yamasaki
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the
increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the develop-
ment of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An effi-
cient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based
on this methodology, novel 15-membered macrolides, known as ‘11a-azalides’, with substituents at the
C12, C13, or C400 positions were synthesized and their antibacterial activities were evaluated. These deriv-
atives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae.
Among them, the C400 substituted derivatives had the most potent activity against erythromycin-resistant
S. pneumoniae.
Received 2 June 2012
Revised 6 August 2012
Accepted 8 August 2012
Available online 16 August 2012
Keywords:
Macrolide antibiotics
Azalide
Erythromycin-resistant
Macrolactonization
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The heteroaryl–alkyl side chain is believed to play a key role in
overcoming resistance caused by ribosome methylation.18–22 To
Macrolide antibiotics1–4 (see Fig. 1 for some structures) are a
safe and effective class of drugs for the treatment of respiratory
tract infections. Erythromycin A (EM-A) 1, a 14-membered macro-
lide antibiotic, has been widely prescribed for more than five dec-
ades. Since EM-A decomposes to antibacterially inactive spiroketal
products5 under acidic conditions in the stomach, its bioavailabil-
ity is relatively low and varies interindividually.6 To improve the
pharmacokinetic profile of EM-A caused by its instability, an en-
teric coating is applied to EM-A tablets and further chemical mod-
ifications of EM-A have been performed.1–4 Second-generation
macrolides, such as clarithromycin7 (CAM) 2 and azithromycin8
(AZM) 3, were investigated in the 1980s and were eventually
launched in the 1990s as a result of these chemical modification ef-
forts. These macrolide antibiotics have been widely prescribed for
more than three decades. Because of their widespread use, the
increasing prevalence of macrolide-resistant pathogens among
clinical isolates has become a public health concern.9–12 The major
mechanisms of resistance against Gram-positive pathogens are
ribosome methylation by erm methyltransferase and efflux by
macrolide efflux pumps (mediated by the mef-gene product).13–15
The third generation macrolide, such as telithromycin 4 and
cethromycin 5, are known to be effective against erythromycin-
resistant strains.16,17 These two ketolides have similar structural
features, such as a 3-keto group and a heteroaryl–alkyl side chain.
overcome these resistance problems, numerous chemical modifi-
cations of EM-A have been attempted continuously.23–25
In a chemobiosynthesis report seeking novel scaffolds by trans-
forming the macrolactone skeleton, the C13 position of EM-A was
suggested to play a key role in improving the antibacterial activity
against resistant pathogens.26,27 However, chemical modification at
the C13 position has been underexplored because of its lack of
chemical reactivity. During the mid 1990s, Waddell28,29 and
Nishida30 independently reported C9–C13 modified EM-A deriva-
tives, synthesized from the original C1–8 or 9 fragment of EM-A
and a newly-prepared C9 or 10–13 fragment. Although this ‘cut
and paste’ methodology seemed to be a universal procedure for
providing structural diversity in the C13 region, the reported
compounds were limited to simple and primitive derivatives. Alter-
natively, a related ring reconstruction methodology using 16-mem-
bered macrolide as the starting material has been reported.31
In our previous paper,32 we presented an efficient method for
reconstructing of the 9-dihydroerythromycin A macrolactone skele-
ton. Based on this methodology, we synthesized a novel class of
15-membered macrolides, known as ‘11a-azalides’, and demon-
strated that their C-12/13 substituents were important for their
antibacterial activities (Fig. 2). These 11a-azalides showed a potent
antibacterial activity against erythromycin-susceptible Streptococ-
cus pnuemoniae and an improved antibacterial activity against
erythromycin-resistant strains. These results encouraged us to ex-
plore the structure–activity relationship of the 11a-azalide skeleton.
Herein, we report the synthesis of 11a-azalides with a substituent
⇑
Corresponding author. Tel.: +81 48 669 3064; fax: +81 48 652 7254.
E-mail address: tomohiro.sugimoto@po.rd.taisho.co.jp (T. Sugimoto).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.08.007

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T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
Scheme 1. Synthetic strategy for producing an 11a-azalide skeleton.
12a–j with LiOH produced seco-acid 13a–j. A macrolactonization
reaction of seco-acids 13a–j yielded the desired 15-membered prod-
ucts 14a–j. When a 6-OH seco-acid was used, a seven-membered
byproduct caused this macrolactonization reaction to have a low
yield.32 This seven-membered byproduct was avoided by using
6-O-methylated seco-acids for this reaction. The deprotection of
the TES groups of 14a–j was achieved using an HF-pyridine treat-
ment to produce the desired C12/13-substituted 11a-azalides
15a–j. A Pd(OH)2-catalyzed hydrogenation step was applied to
deprotect the benzyl group at the C13 position of 14e. A Mitsunobu
reaction33 of the resulting hydroxyl derivative 16 and phenylphe-
nols produced the biphenyl derivatives 15k–m. Stille coupling of
the iodophenoxy group at the C13 position of 15j and pyridylstann-
ane produced pyridylphenyl derivatives 15 n–o.
Figure 1. Structures of macrolide antibiotics.
having aromatic group at the C12, C13, or C400 positions and the
resulting antibacterial activities against erythromycin-resistant S.
pnuemo- niae.
2. Results and discussion
2.1.2. Synthesis of 9-keto or 3-keto derivatives
The synthesis of 9-keto or 3-keto derivatives is shown in
Scheme 3. Selective deprotection of the 20 and 400-hydroxyl groups
of 14a was achieved by treatment with 2 equiv of tetra-n-butylam-
monium fluoride. Protection with an acetyl group and a carboxyb-
enzyl group and the subsequent deprotection of the TES group
yielded 9-OH derivative 17. Acid hydrolysis of 14a and subsequent
carboxybenzylation of 9,20-hydroxyl groups produced 3-OH deriv-
ative 18. Oxidation with Dess–Martin reagent and deprotection of
compounds 17 and 18 yielded keto derivatives 19 and 20. The
3-keto derivative 20 could not be isolated as a single diastereomer
because of the epimerization of the C2 methyl group. There is a
previous report about C2 epimerization.34 Although C2 epimer
was not obtained in case most of 3-keto derivative including teli-
thromycin, C2 epimerization was observed in case of the C6 carba-
mate ketolides. The ease of epimerization is probably dependent
on the structure of ketolide.
2.1. Synthesis of 11a-azalides
The synthetic strategy for producing an 11a-azalide skeleton is
shown in Scheme 1. The 11,12-diol moiety of the EM-A macrolac-
tone skeleton was cleaved oxidatively. After the insertion of an
appropriate functionalized amino alcohol and successive saponifi-
cation of the remaining original C12–13 residue, the resulting acy-
clic skeleton was intramolecularly cyclized by a macrolactonization
reaction.
2.1.1. Synthesis of C12/13 substituted derivatives
Following this synthetic route, C12/13 substituted 11a-azalides
15a–j were synthesized from 9-dihydro-6-O-methylerythromycin A
8 (Scheme 2). The 9,20,400-hydroxyl groups of 8 were selectively pro-
tected by triethylsilyl (TES) groups to produce 11,12-diol 9, which
was then treated with lead tetraacetate to yield an acyclic aldehyde
intermediate 10. Reductive amination of aldehyde 10 with various
aminoalcohols 11a–j and subsequent methylation of the resulting
secondary amine at the 11a-position with formaldehyde produced
the desired seco-ester 12a–j. The above three sequential reactions
were performed in a one-pot manner. Saponification of seco-ester
2.1.3. Synthesis of 9-amino derivatives
The synthesis of 9-amino derivatives is shown in Scheme 4.
Carboxybenzylation of the 9-amino and 20-hydroxyl groups of
9-aminoerythromycin 2135,36 and subsequent deprotection of the
20-hydroxyl groups by heating in methanol produced 9-N-carbo-
benzyloxy product. The 30-dimethylamino group behaves as an
intramolecular catalyst making possible the facile hydrolysis of
the 20-O-carbobenzyloxy group under neutral condition.37 Then
the 20,400-hydroxyl groups were protected by TES groups to produce
11,12-diol derivative 22, and subsequent application of the ring
reconstruction procedure used for 9 yielded the 9-carboxybenzyla-
mino derivative 23a/e. The deprotection of the carboxybenzyl
group produced the 9-amino derivative 24a/e.
2.1.4. Synthesis of C12 substituted derivatives
The transformation of the C12 substituent of 14b is shown in
Scheme 5. The benzyl group of 14b was deprotected using Pd-cata-
lyzed hydrogenation. The resulting hydroxyl derivative 25 was
Figure 2. Structure of 11a-azalides.

T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
5789
Scheme 2. Synthesis of 15a–o. Reagents and conditions: (a) TESCl, imidazole, DMF; (b) Pb(OAc)4, CH2Cl2; (c) 11a–j, NaBH(OAc)3, then HCHO(aq), NaBH(OAc)3; (d) LiOH, THF–
EtOH–H2O; (e) 2,4,6-Cl3C6H2COCl, Et3N, THF then DMAP, CH3CN, and reflux; (f) HF–pyridine, THF; (g) H2, Pd(OH)2, THF; (h) phenylphenol derivatives k–m, DEAD, PPh3, THF;
(i) pyridylstannane derivatives n–o, Pd(PPh3)4, toluene, reflux.
converted to azido derivative 26 with bis(p-nitrophenyl)phospho-
razidate (p-NO2DPPA).38 The reduction of the azido group with
triphenylphosphine and the subsequent reductive amination of 28
produced alkyl or arylmethyl-substituted amino derivatives 29–32.
20-O-acetyl groups and subsequent deprotection of the 9-N-cab-
oxybenzyl groups with Pd-catalyzed hydrogenation yielded the
400-carbamate 35a/e.
2.2. In vitro antibacterial activity of 11a-azalides
2.1.5. Synthesis of 400-carbamate derivatives
The synthesis of 400-carbamate derivatives is shown in Scheme 6.
Compound 23a/e was treated with acetic anhydride to selectively
acylate the 20-hydroxyl groups. Subsequent treatment with CDI in
the presence of NaH produced 400-O-imidazocarbonyl intermediates
33a/e. The intermediates 33a/e were treated with amine 34 to
The in vitro antibacterial activities of the prepared 11a-azalides
were assessed against both erythromycin-susceptible and erythro-
mycin-resistant strains of Streptococcus pneumoniae. Clarithromy-
cin 2 was used for comparison in all the assays. The in vitro
antibacterial activity was reported as the minimum inhibitory con-
centration (MIC) determined using the broth microdilution method
install
a
400-carbamate side chain. The methanolysis of the

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T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
Scheme 3. Synthesis of 9-keto or 3-keto derivatives. Reagents and conditions : (a) n-Bu4NF (2 equiv), THF; (b) Ac2O, acetone; (c) triphosgene, pyridine, CH2Cl2 and then
BnOH; (d) HF-pyridine, THF; (e) Dess–Martin periodinane, CH2Cl2; (f) H2, Pd-C, MeOH; (g) 1 N HCl-EtOH; (h) CbzCl, NaHCO3, CH2Cl2-H2O; (i) Dess–Martin periodinane,
CH2Cl2; (j) H2, Pd-C, MeOH.
Scheme 4. Synthesis of 9-amino derivatives. Reagents and conditions : (a) CbzCl, NaHCO3, CH2Cl2–H2O; (b) MeOH; (c) TESCl, imidazole, DMF; (d) Pb(OAc)4, CH2Cl2; (e)
compound 11a/e, NaBH(OAc)3, then HCHO(aq), NaBH(OAc)3; (f) LiOH, THF–EtOH–H2O; (g) 2,4,6-Cl3C6H2COCl, Et3N, THF, then DMAP, toluene, and reflux; (h) HF–pyridine,
THF; (i) H2, Pd-C, MeOH.
according to the guidelines of the Clinical and Laboratory Stan-
dards Institute (formerly the National Committee of Clinical Labo-
ratory Standards) for S. pneumoniae. S. pneumoniae ATCC49619 is
an erythromycin-susceptible strain, while S. pneumoniae 205 is
an inducible MLSB-resistant strain encoded by the erm(B)
gene.
First, we evaluated the effect of the 11a-azalide aglycon struc-
ture on antibacterial activity (Tables 1 and 2). The 6-O-methyl
derivative 15a (CAM type) had a better antibacterial activity than
the 6-hydroxy derivative 4 (EM-A type). The 9-keto derivative 19
was 16–32-fold less potent than 15a. The 3-keto derivative 20
completely lost its antibacterial activity. The 9-amino derivative
24a showed a similar activity to that of 4.
Next, we evaluated the effect of the introduction of a substitu-
ent to the C12 position of 15a on antibacterial activity (Table 2).
The 12-benzyloxymethyl derivative 15b had a fourfold better
activity against erythromycin-susceptible S. pneumoniae compared
with 15c, which has an opposite stereo chemical configuration at
the 12-position. The 12-benzyloxyethyl derivative 15f had the
same antibacterial activity as 15b. Although the amino derivative
28 and the dialkylamino derivative 29 had poor antibacterial activ-
ities, pyridylmethyl-substituted derivatives 30, 31 had the same
activities as 15b. Especially, the biaryl derivative 32 exhibited an
improved activity against erythromycin-resistant S. pneumoniae,
compared with CAM.
activity (Table 2). At the C13 position, the difference in the stereo-
chemical configuration of the substituent had a significant impact
on the antibacterial activity. The 13-benzyloxymethyl derivative
15e showed a 16-fold better activity against erythromycin-suscep-
tible S. pneumoniae, compared with 15d. Next, we evaluated the
effect of the distance of the phenyl group from aglycon on the
activity against resistant S. pneumoniae. The most active compound
was compound 15i, which has a phenoxymethyl group at the 13-
position. Furthermore, the introduction of a phenyl substituent at
the phenoxymethyl group of 15i increased the activity against
resistant S. pneumoniae. Compound 15m, which has a 4-phenyl-
phenoxymethyl group, had a fourfold greater activity against resis-
tant S. pneumoniae than 15i. Compound 15o, which has a 4-(2-
pyridyl)phenylmethyl group, had an improved activity against
erythromycin-susceptible S. pneumoniae.
Several reports have indicated that the introduction of an aro-
matic side chain at the C-400 position enhances activity against
erythromycin-resistant S. pneumoniae.39,40 Especially, the 400-carba-
mate derivative CP-544372 exhibited a significant in vitro activity
against Gram-positive bacteria including erythromycin-resistant S.
pneumoniae.41 So, we applied a reported 400-carbamate substituent
to 24a/e. The activities of 35a/e against erythromycin-resistant S.
pneumoniae were 256-fold stronger than those of the parent com-
pound 24a/e (Table 1). Although the benzyloxymethyl derivative
24e showed a 16-fold better activity against erythromycin-suscep-
tible S. pneumoniae than 24a, the activities of 35a/e against a resis-
tant strain were almost the same.
Next, we evaluated the effect of the introduction of a substitu-
ent introduction to the C13 position of 15a on the antibacterial

T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
5791
Scheme 5. Synthesis of C12 substituted derivatives. Reagents and conditions : (a) H2, Pd(OH)2, THF; (b) p-NO2-DPPA, DBU, toluene, 50 °C; (c) HF-Pyridine, THF; (d) Ph3P, H2O,
THF; (e) aldehyde, NaBH(OAc)3, CHCl3.
3. Conclusion
A method of synthesizing structurally diverse 11a-azalides was
established. Using this method, 11a-azalides with substituents at
the C12, C13, and C400 positions were synthesized and the antibac-
terial activities of the resulting compounds were evaluated. Among
them, the C12-substituted derivative 32 and the C13-substituted
derivative 15m showed a 16-fold better activity against erythro-
mycin-resistant S. pneumoniae, and their activities were compara-
ble to that of CAM. The C400-substituted derivative 35e showed a
significantly improved activity against an erythromycin-resistant
strain and showed a potent activity against an erythromycin-sus-
ceptible strain, compared with the activities of CAM. These results
reveal that the 11a-azalide scaffold is useful for improving the
antibacterial activity against resistant pathogens.
4. Experimental section
All reactions sensitive to air or moisture were performed in a
nitrogen atmosphere with anhydrous solvents. All the reagents
and solvents were purchased commercially and were used without
purification unless otherwise noted. Column chromatography was
Scheme 6. Synthesis of 400-carbamate derivatives. Reagents and conditions : (a)
Ac2O, acetone; (b) CDI, NaH, THF–DMF, 0 °C; (c) amine 34, THF; (d) MeOH; (e) H2,
Pd-C, MeOH.
performed using a silica gel 60 with a particle size of 40–50
lm.
The 1H and 13C NMR spectra were recorded in CDCl3 on a JEOL Alpha

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T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
Table 1
Antibacterial activities of 11a-azalides
MIC (l
g/mL)
29
4
19
20
24a
24e
28
64
30
31
32
35a
35e
2
S. pneumoniae
ATCC49619a
S. pneumoniae
205b
4
32
>128
2
0.12
>128
128
4
1
0.5
0.12
0.12
0.03
>128
>128
>128
>128
>128
>128
>128
>128
8
0.5
0.25
>128
a
Erythromycin-susceptible strain.
Erythromycin-resistant strain.
b
Table 2
Antibacterial activities of C12/C13-substituted 11a-azalides 15a–o
MIC (
lg/mL)
15a
15b
15c
15d
15e
0.06
15f
15g
0.5
15h
15i
15k
0.5
15l
15m
15n
15o
S. pneumoniae
ATCC49619a
S. pneumoniae
205b
2
1
4
1
1
0.12
128
0.25
32
1
1
0.5
0.25
>128
64
64
64
128
64
>128
16
16
8
64
16
a
Erythromycin-susceptible strain.
Erythromycin-resistant strain.
b
500 or JEOL Lambda 500 spectrometer. Chemical shifts were re-
ported in parts per million (ppm) using tetramethylsilane (TMS)
as an internal standard. Coupling constants (J) were given in hertz
(Hz). Multiplicities were indicated as br (broadened), s (singlet), d
(doublet), t (triplet), q (quartet) or m (multiplet). All assignments
were made using 1H–1H correlation spectroscopy (COSY), hetero-
nuclear multiple-quantum coherence (HMQC), and heteronuclear
multiple-bond correlation (HMBC) methods. Mass spectra (MS)
were obtained with a Micromass Platform LC or a Micromass Q-
Tof 2. The HRMS spectra were obtained with a Shimadzu LCMS-
IT-TOF. The IR spectra were recorded using a PerkinElmer Paragon
1000 spectrometer as KBr pellets and were reported in reciprocal
centimeters (cmꢀ1). Elemental analyses were performed using a
PerkinElmer 2400 CHN analyzer.
7.1, 7.0, 5.5, 5.4, 5.1; IR (KBr) 3456, 2958, 1738, 1459, 740 cmꢀ1
;
HRMS (ESI/APCI-dual, [M+H]+) found 1092.7621, calcd for C56H113
NO13Si3 1092.7593.
4.1.2. Synthesis of aminoalcohols 11a–j
Compounds 11a and 11g were commercially available.
4.1.2.1. Preparation of (R)-2-amino-3-(benzyloxy)propan-1-ol
11b43
.
O-Benzyl-L-serine (15.0 g, 76.8 mmol) was added to a
suspension of lithium aluminum hydride (4.37 g, 115.3 mmol) in
THF (150 mL) under reflux. After stirring at this temperature for
1.5 h, the reaction mixture was cooled in an ice bath, and distilled
water (4.4 mL), 10% aqueous NaOH (4.4 mL) and distilled water
(4.4 mL) were added. After stirring at room temperature for 18 h,
the resulting mixture was filtrated and washed with THF. The sol-
vent was removed in vacuo and the residue was purified using sil-
ica gel chromatography (CHCl3/MeOH/NH4OH = 10:1:0.1) yield
4.1. Synthesis of C12/13 substituted derivatives
4.1.1. Synthesis of 9
amino alcohol 11b (6.43 g, 69%) as a colorless foam: ½a D27
ꢀ5.0 (c
ꢁ
Chlorotriethylsilane (59.4 g, 394.4 mmol) and imidazole (80.6 g,
1183 mmol) were added to a solution of 842 (84.5 g, 112.7 mmol)
in DMF (1000 mL) at room temperature. After stirring at room tem-
perature for 16 h, the reaction mixture was diluted with ethyl ace-
tate (500 mL) and n-hexane (500 mL) and washed with distilled
water (1000 mL). The organic layer was separated and dried over
MgSO4. The solvent was removed in vacuo and the residue was
purified using silica gel chromatography (hexane/acetone = 100:1
to 5:1) to yield compound 9 (107.9 g, 88%) as a colorless foam:
0.760, methanol); 1H NMR (CDCl3) d 7.27–7.41 (m, 5H), 4.53 (s,
2H), 3.39–3.67 (m, 4H), 3.03–3.17 (m, 1H), 1.85 (br s, 3H); 13C
NMR (CDCl3) d 137.9, 128.2, 127.55, 127.50, 73.1, 72.5, 63.7,
52.3; MS (ESI) m/z 182.2 [M+H]+; NMR data consistent with
literature.44
4.1.2.2. Preparation of (S)-2-amino-3-(benzyloxy)propan-1-ol
11c43
.
O-Benzyl-D-serine (10.0 g, 51.2 mmol) was added to a
suspension of lithium aluminum hydride (2.92 g, 76.8 mmol) in
THF (200 mL) under reflux. After stirring at this temperature for
2 h, the reaction mixture was cooled in an ice bath, and distilled
water (2.9 mL), 10% aqueous NaOH (2.9 mL) and distilled water
(2.9 mL) were added. After stirring at room temperature for 18 h,
the resulting mixture was filtrated and washed with THF. The sol-
vent was removed in vacuo and the residue was purified using sil-
ica gel chromatography (CHCl3/MeOH/NH4OH = 10:1:0.1) yield
1H NMR (CDCl3)
d 5.06 (dd, J = 11.1, 2.5 Hz, 1H), 4.84 (d,
J = 5.0 Hz, 1H), 4.46 (s, 1H), 4.30 (d, J = 6.6 Hz, 1H), 4.20–4.26 (m,
1H), 3.86 (d, J = 9.5 Hz, 1H), 3.79 (s, 1H), 3.62 (d, J = 9.1 Hz, 1H),
3.45–3.51 (m, 1H), 3.33 (dd, J = 9.7, 2.3 Hz, 1H), 3.30 (s, 3H), 3.27
(s, 3H), 3.23 (br s, 1H), 3.20 (d, J = 9.1 Hz, 1H), 3.10 (dd, J = 9.9,
7.0 Hz, 1H), 2.81–2.89 (m, 1H), 2.48–2.54 (m, 1H), 2.36 (d,
J = 14.9 Hz, 1H), 2.17 (s, 6H), 2.03–2.11 (m, 1H), 1.91–1.98 (m,
1H), 1.86–1.91 (m, 1H), 1.81 (s, 1H), 1.64–1.69 (m, 1H), 1.58–
1.63 (m, 1H), 1.49 (dd, J = 14.9, 5.0 Hz, 1H), 1.22–1.30 (m, 4H),
0.92–1.19 (m, 44H), 0.84–0.91 (m, 12H), 0.80 (t, J = 7.4 Hz, 3H),
0.51–0.70 (m, 18H); 13C NMR (CDCl3) d 174.2, 103.5, 97.9, 85.9,
82.2, 81.0, 80.2, 78.3, 77.1, 74.4, 73.4, 73.3, 70.7, 67.7, 65.2, 51.0,
49.5, 45.5, 40.9, 39.9, 37.6, 36.5, 33.7, 32.9, 31.6, 29.4, 24.3, 22.6,
22.0, 21.7, 21.5, 19.2, 19.1, 16.3, 15.9, 14.1, 13.4, 10.4, 9.9, 7.2,
amino alcohol 11c (6.43 g, 69%) as a colorless foam: ½a D27
ꢁ
+4.2
(c 1.062, methanol); 1H NMR (CDCl3) d 7.27–7.41 (m, 5H), 4.53
(s, 2H), 3.39–3.67 (m, 4H), 3.03–3.17 (m, 1H), 1.87 (br s, 3H); MS
(ESI) m/z 182.2 [M+H]+.
4.1.2.3. Preparation of (S)-1-amino-3-(benzyloxy)propan-2-ol
11d.
(S)-Benzyl glycidyl ether (1.00 g, 6.09 mmol) was added

T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
5793
to 25% aqueous ammonia (10 mL) at room temperature. After stir-
ring at room temperature for 18 h, the reaction mixture was ex-
tracted with CHCl3 (20 ml ꢂ 3). The combined organic layer was
dried over MgSO4. The solvent was removed in vacuo and the res-
idue was purified using silica gel chromatography (CHCl3/MeOH/
NH4OH = 10:1:0.1) to yield amino alcohol d 11d (810 mg, 73%) as
residue was recrystallized from diethyl ether to yield 11i (794 mg,
53%) as a colorless powder: 1H NMR (CDCl3) d 7.24–7.34 (m, 2H),
6.88–7.01 (m, 3H), 3.91–4.03 (m, 3H), 2.79–3.02 (m, 2H), 1.99 (br
s, 2H); MS (ESI) m/z 168.0 [M+H]+.
4.1.2.8. Preparation of (R)-1-amino-3-(4-iodophenoxy)propan-
a colorless solid: ½a D27
ꢁ
+5.3 (c 1.06, CHCl3) (Lit.45
[
a
]
ꢀ5.1); 1H
2-ol 11j.
(R)-Glycidyl tosylate (1.35 g, 8.99 mmol) was added
D
NMR (CDCl3) d 7.27–7.38 (m, 5H), 4.55 (s, 2H), 3.68–3.83 (m,
1H), 3.39–3.56 (m, 2H), 2.66–2.89 (m, 2H), 1.80 (br s, 2H); MS
(ESI) m/z 182.0 [M+H]+; NMR data consistent with literature.45
to 4-iodophenol (5.62 g, 25.5 mmol) and 60% sodium hydride
(1.02 g, 25.5 mmol) in DMF (50 mL) at 0 °C. After stirring at 0 °C
for 2 h, the reaction was quenched by adding saturated NH4Cl
(20 mL), and the aqueous layer was extracted with ethyl acetate
(20 mL). The combined organic layer was dried over MgSO4. The
solvent was removed in vacuo and the residue was used in the next
reaction without further purification. The residue was added to
25% aqueous ammonia (50 mL) and methanol (20 mL) at room
temperature. After stirring at room temperature for 2 days, the
reaction mixture was filtrated and washed with cold methanol to
yield 11j (7.15 g, 96%) as a colorless powder: 1H NMR (DMSO-d6)
d 7.56 (d, J = 9.1 Hz, 2H), 6.77 (d, J = 9.1 Hz, 2H), 4.99 (br s, 1H),
3.90–3.95 (m, 1H), 3.82–3.87 (m, 2H), 2.64–2.68 (m, 1H), 2.58–
2.62 (m, 1H); 13C NMR (CDCl3) d 158.6, 137.9, 117.3, 82.9, 70.8,
68.0, 52.5; MS (ESI) m/z 294.0 [M+H]+.
4.1.2.4. Preparation of (R)-1-amino-3-(benzyloxy)propan-2-ol
11e.
(R)-Benzyl glycidyl ether (1.00 g, 6.09 mmol) was added
to 25% aqueous ammonia (10 mL) at room temperature. After stir-
ring at room temperature for 18 h, the reaction mixture was ex-
tracted with CHCl3 (20 ml ꢂ 3). The combined organic layer was
dried over MgSO4. The solvent was removed in vacuo and the res-
idue was purified using silica gel chromatography (CHCl3/MeOH/
NH4OH = 10:1:0.1) to yield amino alcohol 11e (670 mg, 61%) as a
colorless solid: ½a D27
ꢁ
+5.6 (c 1.03, CHCl3) (Lit.46
NMR (CDCl3) d 7.27–7.42 (m, 5H), 4.55 (s, 2H), 3.67–3.82 (m,
1H), 3.39–3.55 (m, 2H), 2.65–2.87 (m, 2H), 1.99 (br s, 3H); MS
(ESI) m/z 182.0 [M+H]+; NMR data consistent with literature.45
½
a 2D7 +6.25); 1H
ꢁ
4.1.3. General procedure for the synthesis of C12/13 substituted
azalides (15a–j)
4.1.2.5. Preparation of (S)-2-amino-4-(benzyloxy)butan-1-ol
11f.
Benzylbromide (1.05 g, 6.11 mmol) was added to N-
(750 mg,
Lead tetraacetate (90%, 2.37 g, 4.80 mmol) was added to a solu-
tion of compound 9 (5.00 g, 4.56 mmol) in CHCl3 (80 mL) at 0 °C.
After stirring for 15 minutes at 0 °C, 2-aminoethanol (558 mg,
9.15 mmol) and sodium triacetoxyborohydride (1.45 g, 6.86 mmol)
were added to the reaction mixture. After stirring for 4 h at room
temperature, 37% aqueous formaldehyde solution (1.81 g,
22.9 mmol) and sodium triacetoxyborohydride (1.45 g, 6.86 mmol)
were added to the reaction mixture. After stirring at room temper-
ature for 1 h, the reaction was quenched by adding saturated NaH-
CO3 (80 mL), and the aqueous layer was extracted with CHCl3
(40 mL). The combined organic layer was dried over MgSO4. The
solvent was removed in vacuo to yield crude seco-acid 12a as a col-
orless oil. Ethanol (10 mL), distilled water (10 mL), and lithium
hydroxide monohydrate (288 mg, 6.86 mmol) were added to a
solution of crude seco-acid 12a in THF (30 mL) at room tempera-
ture. After stirring at room temperature for 6 h, the reaction was
quenched by addition of saturated NH4Cl (20 mL). The organic sol-
vent was removed in vacuo and the residual aqueous layer was ex-
tracted with CHCl3 (20 ml ꢂ 3). The combined organic layers were
dried over MgSO4. The solvent was removed in vacuo and the res-
idue was purified using silica gel chromatography (CHCl3/
MeOH = 50:1 to 5:1) to yield compound 13a (2.28 g, 47%) as a col-
orless foam: 1H NMR (CDCl3) d 4.85 (d, J = 4.6 Hz, 1H), 4.47 (d,
J = 6.9 Hz, 1H), 4.23–4.30 (m, 1H), 3.91 (dd, J = 7.1, 1.7 Hz, 1H),
3.81–3.87 (m, 2H), 3.74 (d, J = 7.3 Hz, 1H), 3.59–3.65 (m, 1H),
3.31 (s, 3H), 3.24–3.27 (m, 4H), 3.14–3.21 (m, 2H), 3.06–3.11 (m,
1H), 2.97–3.03 (m, 1H), 2.88–2.94 (m, 1H), 2.66 (s, 3H), 2.60–2.65
(m, 1H), 2.42–2.57 (m, 3H), 2.36 (d, J = 14.9 Hz, 1H), 2.21–2.25
(m, 1H), 2.20 (s, 6H), 1.74–1.82 (m, 1H), 1.55–1.65 (m, 2H), 1.44
(dd, J = 14.9, 5.0 Hz, 1H), 1.30 (s, 3H), 1.27–1.29 (m, 1H), 1.23 (s,
3H), 1.15–1.20 (m, 10H), 1.13 (d, J = 6.9 Hz, 3H), 1.09 (d,
J = 7.3 Hz, 3H), 0.89–1.01 (m, 30H), 0.55–0.70 (m, 18H); 13C NMR
(CDCl3) d 181.9, 102.8, 96.3, 83.0, 81.1, 80.3, 80.0, 77.9, 73.4,
73.2, 67.4, 65.6, 65.1, 61.4, 60.5, 57.2, 50.6, 49.5, 46.5, 43.1, 41.0,
39.8, 37.7, 36.1, 32.9, 31.2, 29.5, 22.3, 21.9, 21.5, 19.9, 19.5, 19.1,
14.2, 10.6, 7.2, 7.1, 7.1, 5.5, 5.5, 5.2.
Boc-(S)-2-(2,2-dimethyloxazolidin-4-yl)ethanol47
3.06 mmol) and 60% sodium hydride (244 mg, 6.11 mmol) in THF
(10 mL) and DMF (0.5 mL) at room temperature. After stirring at
room temperature for 18 h, the reaction was quenched by adding
saturated NH4Cl (20 mL), and the aqueous layer was extracted with
ethyl acetate (20 mL). The combined organic layer was dried over
MgSO4. The solvent was removed in vacuo and the residue was
purified using silica gel chromatography (hexane/ethyl ace-
tate = 10:1) to yield crude benzyl product (910 mg) as a colorless
oil. This benzyl product (910 mg) was dissolved 1 M aqueous
hydrochloric acid (10 mL). After stirring at room temperature for
2 days, the reaction mixture was neutralized with 10% sodium
hydroxide and extracted with CHCl3 (10 ml ꢂ 3). The combined or-
ganic layers were dried over MgSO4. The solvent was removed in
vacuo and the residue was purified using silica gel chromatography
(CHCl3/MeOH/NH4OH = 10:1:0.1) to yield compound 11f (500 mg,
84% for two steps) as a colorless oil: 1H NMR (CDCl3) d 7.24–7.41
(m, 5H), 4.51 (s, 2H), 3.51–3.64 (m, 3H), 3.36 (dd, J = 10.7, 6.8 Hz,
1H), 3.04 (br s, 1H), 1.94 (br s, 2H), 1.54–1.82 (m, 2H); MS (ESI)
m/z 195.1 [M+H]+.
4.1.2.6. Preparation of (S)-1-amino-4-(benzyloxy)butan-2-ol
11h.
(S)-(2-Benzyloxyethyl)oxirane48 (2.60 g, 14.6 mmol)
was added to 25% aqueous ammonia (100 mL) and methanol
(5.0 mL) at room temperature. After stirring at room temperature
for 6 h, the reaction mixture was extracted with ethyl acetate
(50 ml ꢂ 3). The combined organic layer was dried over MgSO4.
The solvent was removed in vacuo and the residue was purified
using silica gel chromatography (CHCl3/MeOH/NH4OH = 10:1:0.1)
to yield amino alcohol 11h (2.62 g, 92%) as a yellowish oil: 1H
NMR (CDCl3) d 7.25–7.40 (m, 5H), 4.53 (s, 2H), 3.62–3.79 (m,
3H), 2.76–2.84 (m, 1H), 2.61 (dd, J = 12.6, 7.8 Hz, 1H), 2.00 (br s,
2H), 1.68–1.80 (m, 2H) ; MS (ESI) m/z 195.1 [M+H]+.
4.1.2.7. Preparation of (R)-1-amino-3-phenoxypropan-2-ol
11i.
(R)-2-(Phenoxymethyl)oxirane (1.35 g, 8.99 mmol) was
Triethylamine (52 mg, 0.516 mmol) and 2,4,6-trichlorobenzoyl
chloride (120 mg, 0.493 mmol) were added to a solution of com-
pound 13a (500 mg, 0.469 mmol) in THF (9.4 mL) at room tempera-
ture. After stirring at room temperature for 2 h, the reaction mixture
was added to a refluxed solution of DMAP (1.20 g, 11.7 mmol) in
added to 25% aqueous ammonia (15 mL) at room temperature.
After stirring at room temperature for 18 h, the reaction mixture
was extracted with CHCl3 (20 ml ꢂ 3). The combined organic layer
was dried over MgSO4. The solvent was removed in vacuo and the

5794
T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
CH3CN (94 mL) for 0.5 h. The reaction mixture was cooled and
washed with saturated NH4Cl (50 mL). The organic layer was dried
over MgSO4. The solvent was removed in vacuo and the residue
was purified using silica gel chromatography (n-hexane/ace-
tone = 20:1) to yield compound 14a (254 mg, 52%) as a colorless
foam: 1H NMR (CDCl3) d 4.74 (d, J = 5.0 Hz, 1H), 4.45 (s, 1H), 4.24–
4.30 (m, 1H), 4.07–4.13 (m, 1H), 3.99–4.06 (m, 2H), 3.70 (d,
J = 6.9 Hz, 1H), 3.58–3.64 (m, 1H), 3.45–3.50 (m, 1H), 3.30 (s, 3H),
3.13–3.21 (m, 5H), 2.79–2.86 (m, 1H), 2.69–2.75 (m, 1H), 2.42–
2.51 (m, 3H), 2.33 (d, J = 14.9 Hz, 1H), 2.23 (s, 3H), 2.19 (s, 6H),
2.11–2.16 (m, 1H), 2.03–2.09 (m, 1H), 1.82–1.90 (m, 2H), 1.52–
1.65 (m, 2H), 1.42–1.47 (m, 1H), 1.31 (s, 3H), 1.25–1.29 (m, 1H),
1.22 (d, J = 6.1 Hz, 3H), 1.10–1.18 (m, 10H), 1.07 (d, J = 7.3 Hz, 3H),
0.90–1.00 (m, 33H), 0.56–0.68 (m, 18H); 13C NMR (CDCl3) d 176.6,
102.8, 96.2, 81.0, 80.1, 78.0, 77.9, 77.3, 77.0, 76.8, 73.4, 73.1, 67.4,
65.8, 65.2, 62.9, 61.8, 57.1, 50.3, 49.4, 45.0, 43.4, 41.5, 41.0, 37.2,
35.9, 29.5, 22.3, 22.0, 21.9, 19.6, 18.9, 16.6, 12.6, 10.8, 7.1, 7.1, 7.0,
5.5, 5.4, 5.2; IR (KBr) 2957, 1734, 1460, 740 cmꢀ1; HRMS (ESI/
APCI-dual, [M+H]+) found 1047.7510, calcd for C54H110N2O11Si3
1047.7490.
4.1.3.2. Compound 15c.
½
a 2D5
ꢁ
ꢀ89.1 (c 0.229, CHCl3); MASS
(ESI) m/z 825.5 [M+H]+; 1H NMR (CDCl3) d 7.26–7.38 (m, 5H),
4.91 (d, J = 4.7 Hz, 1H), 4.47 (d, J = 2.0 Hz, 2H), 4.41 (d, J = 7.2 Hz,
1H), 4.27–4.32 (m, 1H), 4.23 (d, J = 10.9 Hz, 1H), 4.16 (d,
J = 3.9 Hz, 1H), 4.07–4.08 (m, 1H), 3.74 (d, J = 8.1 Hz, 1H), 3.63–
3.68 (m, 1H), 3.58 (dd, J = 9.7, 4.4 Hz, 1H), 3.42–3.54 (m, 2H),
3.37 (dd, J = 9.5, 7.0 Hz, 1H), 3.32 (s, 3H), 3.19 (s, 3H), 3.07–3.11
(m, 1H), 2.88–3.05 (m, 2H), 2.48 (s, 3H), 2.29 (s, 6H), 2.17–2.22
(m, 6H), 1.58–1.93 (m, 3H), 1.53 (dd, J = 15.1, 4.9 Hz, 1H), 1.33 (s,
3H), 1.29 (d, J = 6.4 Hz, 3H), 1.23 (s, 3H), 1.17 (d, J = 7.5 Hz, 3H),
1.10 (d, J = 7.5 Hz, 3H), 0.99–1.03 (m, 5H), 0.85 (d, J = 7.0 Hz, 3H),
0.73 (d, J = 6.5 Hz, 3H); 13C NMR (CDCl3) d 177.5, 138.0, 128.6,
127.9, 127.7, 103.7, 96.4, 80.8, 79.4, 78.6, 78.3, 77.8, 73.5, 72.8,
71.1, 69.0, 65.5, 65.4, 62.5, 62.1, 57.3, 50.1, 49.5, 45.5, 41.9, 41.6,
40.4, 37.1, 35.2, 32.7, 30.9, 30.4, 29.2, 21.8, 21.7, 21.4, 18.2, 15.9,
14.9, 13.7, 11.0; IR (KBr) 3437, 2973, 1733, 1457, 737 cmꢀ1; HRMS
(ESI/APCI-dual, [M+H]+) found 825.5496, calcd for C44H76N2O12
825.5471.
4.1.3.3. Compound 15d.
½
a 2D5
ꢁ
ꢀ109.7 (c 0.275, CHCl3); MASS
Hydrogen fluoride–pyridine (70%, 37 mg, 1.29 mmol) was
added to a solution of compound 14a (450 mg, 0.429 mmol) in
THF (10.0 mL) at room temperature. After stirring at room temper-
ature for 18 h, the reaction was neutralized with saturated NaHCO3
(10.0 mL). The resulting mixture was diluted with ethyl acetate
(20 mL) and then separated. The organic layer was dried over
MgSO4. The solvent was removed in vacuo and the residue was
purified using silica gel chromatography (CHCl3/MeOH/NH4OH =
10:1:0.1) to yield compound 15a (300 mg, 99%) as a colorless
(ESI) m/z 825.4 [M+H]+; 1H NMR (CDCl3) d 7.24–7.37 (m, 5H),
5.26–5.36 (m, 1H), 4.92 (d, J = 4.51 Hz, 1H), 4.54 (m, 1H), 4.47 (d,
J = 12.12 Hz, 1H), 4.39 (d, J = 7.31 Hz, 1H), 4.35 (d, J = 6.37 Hz,
1H), 4.08 (m, 1H), 3.72 (d, J = 7.77 Hz, 1H), 3.59 (dd, J = 8.47,
2.41 Hz, 1H), 3.42–3.55 (m, 3H), 3.32 (s, 3H), 3.24 (s, 3H), 3.17–
3.27 (m, 1H), 3.10 (s, 1H), 3.01 (t, J = 9.56 Hz, 1H), 2.81–2.96 (m,
2H), 2.30 (s, 6H), 2.18–2.61 (m, 9H), 1.97 (dd, J = 12.20, 3.50 Hz,
1H), 1.59–1.92 (m, 5H), 1.52 (dd, J = 14.92, 4.82 Hz, 1H), 1.31 (d,
J = 6.37 Hz, 3H) 1.33 (s, 3H), 1.23 (d, J = 6.06 Hz, 3H), 1.23 (s, 3H),
1.17 (d, J = 7.46 Hz, 3H), 1.14–1.35 (m, 2H), 1.08 (d, J = 7.31 Hz,
3H), 0.82 (d, J = 6.99 Hz, 3H), 0.70 (d, J = 6.68 Hz, 3H); 13C NMR
(CDCl3) d 176.5, 137.9, 128.4, 127.7, 127.7, 103.5, 96.1, 80.0, 79.4,
78.4, 78.2, 73.4, 72.7, 71.3, 70.4, 68.7, 68.2, 65.4, 65.1, 62.9, 58.6,
50.0, 49.5, 45.4, 44.3, 41.7, 40.4, 37.1, 35.0, 32.7, 30.5, 29.5, 22.7,
21.6, 21.4, 18.3, 15.1, 10.4; IR (KBr) 3460, 2973, 1733, 1458,
737 cmꢀ1; HRMS (ESI/APCI-dual, [M+H]+) found 825.5490, calcd
for C44H76N2O12 825.5471.
foam: ½a 2D6
ꢁ
ꢀ99.7 (c 0.108, CHCl3); MASS (ESI) m/z 705.5 [M+H]+;
1H NMR (CDCl3) d 4.90 (d, J = 4.9 Hz, 1H), 4.41 (d, J = 7.3 Hz, 1H),
4.29–4.37 (m, 1H), 4.25 (d, J = 3.7 Hz, 1H), 4.03–4.12 (m, 1H),
3.91–3.99 (m, 1H), 3.74 (d, J = 7.3 Hz, 1H), 3.58–3.66 (m, 1H),
3.43–3.52 (m, 1H), 3.33 (s, 3H), 3.16–3.26 (m, 5H), 3.01 (t,
J = 9.8 Hz, 1H), 2.88–2.96 (m, 1H), 2.74–2.84 (m, 1H), 2.33–2.51
(m, 5H), 2.32 (s, 3H), 2.30 (s, 6H), 2.18–2.28 (m, 2H), 2.11 (dd,
J = 12.5, 4.6 Hz, 1H), 1.86–1.93 (m, 1H), 1.73–1.80 (m, 1H), 1.63–
1.68 (m, 1H), 1.54 (dd, J = 15.3, 4.9 Hz, 1H), 1.34 (s, 3H), 1.29 (d,
J = 6.1 Hz, 3H), 1.20–1.27 (m, 7H), 1.18 (d, J = 7.3 Hz, 3H), 1.10 (d,
J = 7.3 Hz, 3H), 0.87 (d, J = 7.3 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H); 13C
NMR (CDCl3) d 177.5, 103.6, 96.2, 80.7, 79.4, 78.4, 78.3, 77.9,
72.8, 71.2, 69.0, 65.5, 65.4, 62.9, 61.0, 56.3, 50.1, 49.5, 45.2, 44.1,
42.0, 40.5, 37.0, 35.1, 34.0, 30.9, 29.3, 21.9, 21.7, 21.4, 18.3, 15.1,
13.7, 10.6, 6.6, 5.8; IR (KBr) 3469, 2974, 1733, 1461 cmꢀ1; HRMS
(ESI/APCI-dual, [M+H]+) found 705.4903, calcd for C36H68N2O11
705.4896.
4.1.3.4. Compound 15e.
½
a 2D5
ꢁ
ꢀ40.0 (c 0.219, CHCl3); MASS
(ESI) m/z 825.5 [M+H]+; 1H NMR (CDCl3) d 7.24–7.37 (m, 5H),
4.91–5.01 (m, 1H), 4.80 (d, J = 4.35 Hz, 1H), 4.57 (d, J = 11.97 Hz,
1H), 4.41–4.48 (m, 2H), 4.03–4.14 (m, 1H), 3.88 (d, J = 6.84 Hz,
1H), 3.54–3.60 (m, 2H), 3.42–3.53 (m, 2H), 3.26 (s, 3H), 3.23 (s,
3H), 3.18–3.28 (m, 3H), 2.87–3.03 (m, 3H), 2.43–2.55 (m, 3H),
2.29 (s, 6H), 2.26 (s, 3H), 2.16–2.34 (m, 3H), 1.93 (m, 1H), 1.77–
1.91 (m, 1H), 1.60–1.72 (m, 2H), 1.33 (s, 3H), 1.28 (d, J = 6.22 Hz,
3H), 1.24 (d, J = 6.22 Hz, 3H), 1.19 (d, J = 6.99 Hz, 3H), 1.16 (s,
3H), 1.14 (d, J = 7.31 Hz, 3H), 1.10–1.36 (m, 2H), 0.94 (d,
J = 6.99 Hz, 3H), 0.93 (d, J = 6.53 Hz, 3H); 13C NMR (CDCl3) d
174.7, 138.1, 128.5, 127.8, 104.1, 97.0, 80.8, 79.2, 78.8, 78.1, 73.3,
72.7, 71.9, 71.1, 70.2, 69.1, 65.8, 65.4, 59.1, 49.8, 49.5, 45.8, 44.6,
40.5, 39.4, 37.7, 35.4, 34.1, 31.0, 29.3, 21.6, 21.4, 21.1, 18.2, 16.9,
11.5; IR (KBr) 3469, 2973, 1730, 1457, 736 cmꢀ1; HRMS (ESI/
APCI-dual, [M+H]+) found 825.5483, calcd for C44H76N2O12
825.5471.
Using the general procedure described above, the following
compounds (15b–j) were also prepared:
4.1.3.1. Compound 15b.
MASS (ESI) m/z 825.5 [M+H]+; 1H
NMR (CDCl3) d 7.25–7.38 (m, 5H), 4.81 (d, J = 4.2 Hz, 1H), 4.49 (s,
2H), 4.44 (d, J = 7.3 Hz, 1H), 4.24 (dd, J = 11.9, 3.0 Hz, 1H), 4.03–
4.14 (m, 1H), 3.95 (dd, J = 12.0, 9.0 Hz, 1H), 3.83 (d, J = 7.5 Hz,
1H), 3.57–3.64 (m, 2H), 3.35–3.54 (m, 3H), 3.31 (s, 3H), 3.21 (s,
3H), 2.95 (s, 4H), 2.29 (s, 6H), 2.26 (s, 3H), 2.20–2.22 (m, 5H),
2.07–2.17 (m, 1H), 1.91–1.99 (m, 1H), 1.42–1.83 (m, 3H), 1.33 (s,
3H), 1.27 (d, J = 6.2 Hz, 3H), 1.24 (d, J = 6.1 Hz, 3H), 1.21 (s, 3H),
1.17 (d, J = 7.5 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H), 1.03–1.05 (m, 2H),
0.89 (d, J = 7.2 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3) d
176.6, 138.1, 128.5, 127.8, 127.7, 104.0, 96.8, 80.9, 80.0, 78.6,
78.3, 78.2, 73.5, 72.8, 71.0, 69.2, 67.4, 65.7, 65.4, 63.4, 62.4, 50.0,
49.5, 45.0, 40.9, 40.4, 37.4, 35.7, 35.4, 34.4, 31.3, 29.1, 21.7, 21.4,
21.3, 18.1, 15.4, 14.8, 12.2, 11.9; HRMS (ESI/APCI-dual, [M+H]+)
found 825.5474, calcd for C44H76N2O12 825.5471.
4.1.3.5. Compound 15f.
½
a 2D5
ꢁ
ꢀ56.8 (c 0.359, CHCl3); MASS
(ESI) m/z 839.7 [M+H]+; 1H NMR (CDCl3) d 7.25–7.38 (m, 5H),
4.82 (d, J = 4.5 Hz, 1H), 4.50 (s, 2H), 4.46 (d, J = 7.3 Hz, 1H), 4.39–
4.44 (m, 1H), 4.02–4.17 (m, 2H), 3.79–3.88 (m, 2H), 3.53 (t,
J = 6.4 Hz, 2H), 3.39–3.40 (m, 3H), 3.31 (s, 3H), 3.22 (s, 3H), 2.95
(s, 4H), 2.44–2.64 (m, 3H), 2.29 (s, 6H), 2.19 (s, 3H), 2.05–2.07
(m, 3H), 1.93–2.02 (m, 1H), 1.43–1.90 (m, 5H), 1.33 (s, 3H), 1.28
(d, J = 6.4 Hz, 3H), 1.24 (d, J = 6.1 Hz, 3H), 1.21 (s, 3H), 1.18 (d,

T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
5795
J = 7.3 Hz, 3H), 1.13 (d, J = 7.3 Hz, 3H), 1.04 (s, 2H), 0.91 (d,
J = 7.0 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3) d 176.3,
138.4, 128.5, 127.8, 127.8, 103.9, 96.4, 81.0, 80.3, 78.5, 78.2, 77.4,
77.1, 76.8, 73.2, 72.8, 71.0, 69.2, 68.0, 65.6, 65.4, 64.0, 61.4, 50.0,
49.5, 44.6, 40.4, 37.4, 35.3, 34.1, 33.9, 30.4, 29.1, 27.2, 21.7, 21.4,
21.1, 18.1, 15.9, 12.3, 11.9; IR (KBr) 3392, 2977, 1726, 1464,
741 cmꢀ1; HRMS (ESI/APCI-dual, [M+H]+) found 839.5643, calcd
for C45H78N2O12 839.5628.
1.33 (m, 17H), 0.94–0.99 (m, 6H); 13C NMR (CDCl3) d 174.5,
158.5, 138.3, 117.0, 103.8, 97.2, 83.2, 80.8, 79.7, 79.0, 77.9, 72.5,
71.5, 70.9, 69.0, 67.8, 65.7, 65.3, 49.9, 49.4, 46.0, 44.8, 40.4, 39.2,
37.6, 36.6, 35.4, 34.0, 30.9, 29.2, 21.5, 21.4, 21.4, 21.0, 18.2, 16.9,
12.0, 11.5; IR (KBr) 3468, 2973, 1732, 1588, 1488, 820 cmꢀ1; HRMS
(ESI/APCI-dual, [M+H]+) found 937.4305, calcd for C43H73IN2O12
937.4281.
4.1.4. General procedure for the synthesis of compound 15k–m
A mixture of 14e (12.9 g, 11.0 mmol) and 20% Pd(OH)2 (25.0 g)
in THF (130 mL) was stirred in a hydrogen atmosphere at room
temperature for 18 h. After the removal of insoluble particles using
filtration, the solvent was removed in vacuo and the residue was
purified using silica gel chromatography (hexane/acetone = 5:1)
to yield compound 16 (6.24 g, 53%) as a colorless foam: MASS
(ESI) m/z 1077.7 [M+H]+; 1H NMR (CDCl3) d 4.97–5.11 (m, 1H),
4.76 (d, J = 4.1 Hz, 1H), 4.43 (d, J = 7.0 Hz, 1H), 4.22–4.30 (m, 1H),
3.65–3.77 (m, 3H), 3.57–3.64 (m, 1H), 3.34–3.43 (m, 1H), 3.29 (s,
3H), 3.25 (s, 3H), 3.14–3.22 (m, 3H), 2.74–2.83 (m, 1H), 2.27–
2.64 (m, 9H), 2.21 (br s, 6H), 2.02–2.11 (m, 1H), 1.90–1.99 (m,
1H), 1.77–1.85 (m, 1H), 1.58–1.70 (m, 1H), 1.40–1.50 (m, 2H),
1.32 (s, 3H), 1.04–1.26 (m, 23H), 0.90–1.01 (m, 27H), 0.54–0.71
(m, 18H); 13C NMR (CDCl3) d 174.4, 103.1, 96.0, 80.9, 80.7, 77.8,
73.3, 73.2, 67.5, 65.6, 65.4, 64.0, 63.0, 58.9, 49.9, 49.5, 46.0, 41.0,
39.6, 36.1, 29.6, 22.2, 21.7, 20.1, 18.9, 11.4, 7.1, 7.0, 5.5, 5.4, 5.2;
HRMS (ESI/APCI-dual, [M+H]+) found 1077.7626, calcd for
4.1.3.6. Compound 15g.
½
a 2D5
ꢁ
ꢀ29.1 (c 0.102, CHCl3); MASS
(ESI) m/z 781.4 [M+H]+; 1H NMR (CDCl3) d 7.23–7.40 (m, 5H),
5.66 (dd, J = 9.40, 3.65 Hz, 1H), 4.61 (s, 1H), 4.51 (d, J = 4.04 Hz,
1H), 4.47 (d, J = 7.15 Hz, 2H), 3.91–4.10 (m, 2H), 3.63–3.73 (m,
1H), 3.41–3.55 (m, 2H), 3.32 (s, 3H), 3.17 (s, 3H), 3.14–3.36 (m,
2H), 2.99–3.08 (m, 1H), 2.85–2.94 (m, 1H), 2.43–2.59 (m, 3H),
2.30 (s, 6H), 2.27 (s, 3H), 2.22–2.34 (m, 2H), 1.84–2.09 (m, 3H),
1.72–1.82 (m, 1H), 1.62–1.71 (m, 1H), 1.36 (s, 3H), 1.27 (d,
J = 5.75 Hz, 3H), 1.25 (d, J = 5.75 Hz, 3H), 1.17 (d, J = 7.15 Hz, 3H),
1.14 (d, J = 7.31 Hz, 3H), 1.07 (s, 3H), 1.05–1.40 (m, 2H), 0.90–
1.02 (m, 6H); 13C NMR (CDCl3) d 174.4, 139.4, 128.6, 128.2,
127.0, 104.4, 97.0, 81.1, 79.6, 78.5, 78.1, 74.5, 72.5, 71.1, 69.2,
65.6, 65.4, 63.9, 49.9, 49.5, 45.5, 43.8, 40.5, 39.5, 38.1, 35.2, 34.3,
31.1, 29.4, 21.6, 21.4, 21.1, 18.1, 17.3, 12.1, 11.4; IR (KBr) 3462,
2973, 1734, 1458, 760 cmꢀ1; HRMS (ESI/APCI-dual, [M+H]+) found
781.5230, calcd for C42H72N2O11 781.5209.
4.1.3.7. Compound 15h.
½
a 3D1
ꢁ
ꢀ41.4 (c 0.149, CHCl3); MASS
C55H112N2O12Si3 1077.7596.
(ESI) m/z 839.6 [M+H]+; 1H NMR (CDCl3) d 7.25–7.35 (m, 5H),
4.89–4.98 (m, 1H), 4.79 (d, J = 4.2 Hz, 1H), 4.48–4.54 (m, 1H),
4.45–4.47 (m, 1H), 4.43 (d, J = 7.3 Hz, 1H), 4.33–4.39 (m, 1H),
4.03–4.16 (m, 1H), 3.89 (d, J = 6.4 Hz, 1H), 3.41–3.55 (m, 6H),
3.28 (s, 3H), 3.26–3.27 (m, 1H), 3.25 (s, 3H), 2.90–3.06 (m, 3H),
2.85 (dd, J = 13.5, 7.8 Hz, 1H), 2.30 (s, 6H), 2.25 (s, 3H), 2.14–2.23
(m, 6H), 1.60–2.04 (m, 5H), 1.49 (dd, J = 14.7, 5.2 Hz, 1H), 1.32 (s,
3H), 1.28 (d, J = 6.1 Hz, 3H), 1.24 (d, J = 6.1 Hz, 3H), 1.20 (s, 3H),
1.10–1.16 (m, 6H), 0.89–0.97 (m, 6H); 13C NMR (CDCl3) d 174.6,
138.2, 128.4, 128.3, 127.7, 127.6, 127.6, 104.3, 96.5, 80.7, 78.9,
78.0, 73.1, 72.6, 71.0, 69.0, 66.8, 65.3, 62.5, 49.8, 49.5, 45.3, 40.5,
39.2, 37.5, 35.3, 33.8, 33.5, 30.9, 29.5, 21.7, 21.4, 21.0, 18.3, 11.1;
IR (KBr) 3469, 2973, 1728, 1458, 737 cmꢀ1; HRMS (ESI/APCI-dual,
[M+H]+) found 839.5630, calcd for C45H78N2O12 839.5628.
Diethyl azodicarboxylate (0.19 g, 1.10 mmol) was added to a
solution of compound 16 (396 mg, 0.367 mmol), triphenylphos-
phine (0.29 g, 1.10 mmol) and o-phenylphenol (0.19 g, 1.10 mmol)
in THF (8 mL) at room temperature. After stirring at room temper-
ature for 18 h, the solvent was removed in vacuo and the residue
was diluted with diethyl ether (60 mL) and washed with saturated
NaHCO3 (30 mL) and brine (30 mL). The organic layer was dried
over MgSO4. The solvent was removed in vacuo to yield a crude
product as yellow oil. Hydrogen fluoride–pyridine (70%, 105 mg,
3.67 mmol) was added to a solution of the crude product in THF
(10 mL) at room temperature. After stirring at room temperature
for 18 h, the reaction was neutralized with saturated NaHCO3
(20 mL). The resulting mixture was diluted with ethyl acetate
(60 mL) and then separated. The organic layer was dried over
MgSO4. The solvent was removed in vacuo and the residue was
purified using silica gel chromatography (CHCl3/MeOH/
NH4OH = 10:1:0.1) to yield compound 15k (39 mg, 12% for two
4.1.3.8. Compound 15i.
MASS (ESI) m/z 811.4 [M+H]+; 1H
NMR (CDCl3) d 7.23–7.30 (m, 2H), 6.95 (t, J = 7.3 Hz, 2H), 6.87 (d,
J = 7.9 Hz, 1H), 5.04 (d, J = 3.7 Hz, 1H), 4.77 (d, J = 4.3 Hz, 1H),
4.47 (d, J = 7.3 Hz, 1H), 4.18 (dd, J = 10.4, 3.7 Hz, 1H), 4.00–4.07
(m, 2H), 3.91 (d, J = 7.3 Hz, 1H), 3.45–3.57 (m, 2H), 3.35 (d,
J = 9.2 Hz, 1H), 3.30 (s, 3H), 3.25–3.27 (m, 1H), 3.22 (s, 3H), 2.92–
3.17 (m, 3H), 2.84 (t, J = 8.9 Hz, 1H), 2.59 (dd, J = 14.0, 3.7 Hz,
1H), 2.42–2.56 (m, 3H), 2.30 (s, 3H), 2.29 (s, 6H), 1.81–2.15 (m,
5H), 1.54–1.70 (m, 2H), 1.35 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.14
(d, J = 7.3 Hz, 3H), 0.93–1.38 (m, 17H); 13C NMR (CDCl3) d 174.0,
158.7, 129.6, 121.2, 114.6, 104.1, 97.5, 81.0, 79.9, 78.0, 72.6, 71.7,
71.0, 69.1, 68.7, 67.6, 65.7, 65.4, 49.9, 49.5, 46.2, 40.5, 39.4, 37.8,
35.5, 34.3, 30.9, 29.1, 21.4, 21.4, 21.0, 18.1, 16.8, 11.8, 7.2, 5.6;
HRMS (ESI/APCI-dual, [M+H]+) found 811.5314, calcd for
steps) as a colorless foam: ½a D31
ꢀ17.3 (c 0.208, CHCl3); MASS
ꢁ
(ESI) m/z 887.4 [M+H]+; 1H NMR (CDCl3) d 7.46–7.56 (m, 2H),
7.22–7.44 (m, 5H), 6.92–7.10 (m, 2H), 4.91–5.02 (m, 1H), 4.72 (d,
J = 4.40 Hz, 1H), 4.43 (d, J = 7.03 Hz, 1H), 4.24–4.34 (m, 1H), 3.98–
4.22 (m, 3H), 3.83 (d, J = 7.91 Hz, 1H), 3.25 (s, 3H), 3.15 (s, 3H),
3.11–3.57 (m, 5H), 2.80–3.00 (m, 3H), 2.28 (s, 6H), 2.19 (s, 3H),
2.08–2.66 (m, 8H), 1.58–2.00 (m, 4H), 0.89–1.40 (m, 26H); 13C
NMR (CDCl3) d 174.3, 155.4, 138.3, 131.1, 130.9, 129.7, 128.6,
127.8, 126.9, 121.4, 112.5, 103.8, 97.1, 80.6, 80.0, 79.3, 78.0, 77.3,
77.0, 76.8, 72.5, 72.0, 71.0, 69.0, 67.9, 65.6, 65.4, 58.2, 49.8, 49.4,
45.9, 44.8, 40.4, 39.0, 37.4, 35.5, 33.8, 30.7, 29.7, 29.1, 21.4, 21.4,
21.1, 18.3, 16.8, 12.4, 11.4; IR (KBr) 3468, 2972, 1730, 1600,
1459, 754 cmꢀ1; HRMS (ESI/APCI-dual, [M+H]+) found 887.5657,
calcd for C49H78N2O12 887.5628.
C43H74N2O12 811.5315.
4.1.3.9. Compound 15j.
½
a 2D5
ꢁ
ꢀ32.8 (c 0.121, CHCl3); MASS
(ESI) m/z 937.4 [M+H]+; 1H NMR (CDCl3) d 7.54 (d, J = 8.9 Hz, 2H),
6.67 (d, J = 8.6 Hz, 2H), 4.98–5.04 (m, 1H), 4.73–4.77 (m, 1H),
4.45 (d, J = 7.2 Hz, 1H), 3.99–4.18 (m, 4H), 3.88 (d, J = 7.2 Hz, 1H),
3.44–3.56 (m, 2H), 3.29 (s, 3H), 3.20–3.26 (m, 4H), 2.95–3.15 (m,
2H), 2.90 (d, J = 9.3 Hz, 1H), 2.45–2.61 (m, 4H), 2.31 (s, 6H), 2.29
(s, 3H), 2.17–2.25 (m, 1H), 2.12 (d, J = 15.1 Hz, 1H), 1.95–2.03 (m,
1H), 1.79–1.89 (m, 1H), 1.65–1.73 (m, 1H), 1.35 (s, 3H), 1.04–
4.1.4.1. Compound 15l.
Compound 15l (87 mg, 22% for two
steps) was prepared from compound 16 (473 mg, 0.439 mmol)
according to the procedure used to prepare 15k: ½a D25
ꢀ24.1 (c
ꢁ
0.123, CHCl3); MASS (ESI) m/z 887.3 [M+H]+; 1H NMR (CDCl3) d
7.52–7.60 (m, 2H), 7.39–7.46 (m, 2H), 7.29–7.38 (m, 2H), 7.15–
7.21 (m, 1H), 7.09 (m, 1H), 6.85 (dd, J = 7.77, 2.18 Hz, 1H), 5.02–
5.10 (m, 1H), 4.78 (d, J = 4.66 Hz, 1H), 4.58–4.67 (m, 1H), 4.46 (d,

5796
T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
J = 7.31 Hz, 1H), 4.25 (dd, J = 10.49, 3.34 Hz, 1H), 4.10 (dd, J = 10.26,
3.57 Hz, 1H), 4.03 (dd, J = 9.56, 6.14 Hz, 1H), 3.91 (d, J = 7.62 Hz,
1H), 3.42–3.62 (m, 3H), 3.32 (s, 3H), 3.21 (s, 3H), 3.12–3.27 (m,
2H), 2.97–3.07 (m, 1H), 2.73–2.83 (m, 1H), 2.61 (dd, J = 13.99,
4.20 Hz, 1H), 2.42–2.66 (m, 2H), 2.31 (s, 3H), 2.29 (s, 6H), 2.17–
2.35 (m, 2H), 1.97–2.10 (m, 2H), 1.82–1.93 (m, 2H), 1.62–1.71
(m, 1H), 1.36 (s, 3H), 1.25 (d, J = 6.22 Hz, 3H), 1.23 (s, 3H), 1.22
(d, J = 6.22 Hz, 3H), 1.19 (d, J = 6.99 Hz, 3H), 1.15 (d, J = 7.15 Hz,
3H), 1.11–1.40 (m, 2H), 0.91–1.01 (m, 6H); 13C NMR (CDCl3) d
174.9, 159.1, 143.0, 141.0, 129.9, 128.9, 127.7, 127.3, 120.2,
113.8, 113.1, 104.1, 97.6, 81.0, 79.7, 78.8, 78.0, 72.6, 71.7, 71.0,
69.1, 67.8, 65.7, 65.5, 49.9, 49.5, 46.3, 40.4, 39.5, 37.9, 35.5, 34.4,
31.0, 29.2, 21.4, 21.4, 21.0, 18.0, 16.8, 11.9; IR (KBr) 3469, 2973,
1732, 1599, 1460, 759 cmꢀ1; HRMS (ESI/APCI-dual, [M+H]+) found
887.5654, calcd for C49H78N2O12 887.5628.
1H NMR (CDCl3) d 8.63–8.66 (m, 1H), 7.94 (d, J = 9.1 Hz, 2H),
7.69–7.73 (m, 1H), 7.67 (s, 1H), 7.16–7.19 (m, 1H), 7.01 (d,
J = 9.1 Hz, 2H), 4.69 (d, J = 5.0 Hz, 1H), 4.45 (d, J = 7.0 Hz, 1H),
4.13–4.18 (m, 1H), 4.01–4.07 (m, 3H), 3.71 (d, J = 5.0 Hz, 1H),
3.67 (s, 3H), 3.45–3.53 (m, 2H), 3.30 (s, 3H), 3.23–3.28 (m, 2H),
3.22 (s, 3H), 2.96–3.02 (m, 1H), 2.72–2.79 (m, 2H), 2.60–2.66 (m,
1H), 2.47–2.54 (m, 1H), 2.38 (br s, 3H), 2.24–2.35 (m, 8H), 1.81–
1.93 (m, 2H), 1.64–1.75 (m, 2H), 1.46–1.54 (m, 1H), 1.30 (s, 3H),
1.27 (s, 3H), 1.23 (d, J = 5.8 Hz, 3H), 1.22 (s, 3H), 1.20–1.29 (m,
2H), 1.14 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 7.4 Hz, 3H), 0.88 (d,
J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3) d 176.2,
159.5, 157.1, 149.6, 136.7, 132.4, 128.2, 121.5, 119.8, 114.8,
102.7, 95.4, 80.5, 80.0, 78.9, 78.6, 78.1, 72.8, 71.0, 70.5, 69.1, 67.0,
65.4, 64.9, 61.0, 51.7, 50.0, 49.4, 43.6, 41.8, 40.4, 37.5, 37.2, 35.2,
32.8, 30.6, 29.1, 21.7, 21.3, 20.7, 18.1, 14.7, 14.1, 11.3, 10.9; HRMS
(ESI/APCI-dual, [M+H]+) found 888.5620, calcd for C48H77N3O12
888.5580.
4.1.4.2. Compound 15m.
Compound 15m (101 mg, 36% for
two steps) was prepared from compound 16 (340 mg, 0.315 mmol)
according to the procedure used to prepare 15k: ½a D25
ꢁ
ꢀ24.0
4.2. Synthesis of 9-keto or 3-keto derivatives
(c 0.053, CHCl3); MASS (ESI) m/z 887.5 [M+H]+; 1H NMR (CDCl3) d
7.46–7.56 (m, 4H), 7.37–7.45 (m, 2H), 7.27–7.34 (m, 1H), 6.90–
6.98 (m, 2H), 5.01–5.10 (m, 1H), 4.79 (d, J = 4.20 Hz, 1H), 4.50–
4.61 (m, 1H), 4.47 (d, J = 7.15 Hz, 1H), 4.23 (dd, J = 10.57, 3.57 Hz,
1H), 4.01–4.13 (m, 2H), 3.91 (d, J = 6.99 Hz, 1H), 3.42–3.61 (m,
3H), 3.32 (s, 3H), 3.23 (s, 3H), 3.09–3.36 (m, 2H), 2.97–3.07 (m,
1H), 2.79–2.90 (m, 1H), 2.61 (dd, J = 14.22, 4.27 Hz, 1H), 2.42–
2.67 (m, 3H), 2.31 (s, 3H), 2.29 (s, 6H), 2.19–2.36 (m, 2H), 1.81–
2.14 (m, 4H), 1.62–1.72 (m, 1H), 1.36 (s, 3H), 1.27 (d, J = 4.66 Hz,
3H), 1.25 (d, J = 4.66 Hz, 3H), 1.19 (d, J = 7.15 Hz, 3H), 1.15 (d,
J = 7.15 Hz, 3H), 1.08–1.40 (m, 2H), 1.01 (s, 3H), 0.97 (d,
J = 6.37 Hz, 3H), 0.96 (d, J = 6.53 Hz, 3H); 13C NMR (CDCl3) d
174.9, 158.3, 140.8, 134.5, 128.9, 128.3, 126.9, 115.0, 104.0, 97.5,
81.0, 79.9, 78.0, 72.6, 71.0, 69.1, 67.9, 65.9, 65.7, 65.5, 49.9, 49.5,
46.2, 40.4, 39.4, 37.8, 35.5, 34.3, 31.0, 29.1, 21.4, 21.0, 18.2, 16.9,
15.3, 11.8; IR (KBr) 3469, 2973, 1731, 1611, 1459, 764 cmꢀ1; HRMS
(ESI/APCI-dual, [M+H]+) found 887.5656, calcd for C49H78N2O12
887.5628.
4.2.1. Synthesis of compound 19
Tetra-n-butylammonium fluoride (1.0 M THF solution, 6.68 ml,
6.68 mmol) was added to a solution of compound 14a (3.50 g,
3.34 mmol) in THF (50 mL) at room temperature. After stirring at
room temperature for 18 h, the reaction was diluted with ethyl
acetate (50 mL) and washed with brine (100 mL). The organic layer
was separated and dried over MgSO4. The solvent was removed in
vacuo and the residue was purified using silica gel chromatography
(CHCl3/MeOH/NH4OH = 30:1:0.1) to yield the 20,400-hydroxy prod-
uct (1.44 g, 53%), resembling a colorless foam. Acetic anhydride
(349 mg, 3.42 mmol) was added to a solution of this 20,400-hydroxy
product (1.40 g, 1.71 mmol) in acetone (10 mL) at room tempera-
ture. After stirring at room temperature for 18 h, the reaction
was diluted with ethyl acetate (20 mL) and saturated NaHCO3
(20 mL). The organic layer was separated and dried over MgSO4.
The solvent was removed in vacuo to yield crude 20-O-acetyl prod-
uct as a colorless foam. Benzyl alcohol (1.56 ml, 15.1 mmol) was
added to a solution of this 20-O-acetyl product, pyridine (1.10 ml,
13.6 mmol) and triphosgene (671 mg, 2.26 mmol) in CH2Cl2
(20 mL) at 0 °C. After stirring for 15 minutes at 0 °C, the reaction
was quenched by adding distilled water (20 mL), and the aqueous
layer was extracted with CHCl3 (20 mL). The combined organic
layer was dried over MgSO4. The solvent was removed in vacuo
and the residue was purified using silica gel chromatography
(CHCl3/MeOH/NH4OH = 10:1:0.1) to yield a 400-O-benzyloxycar-
bonyl product (1.60 g, 94% from 20,400-hydroxy product) , resem-
4.1.4.3. Compound 15n.
Tetrakis(triphenylphosphine)palla-
dium (12 mg, 0.0107 mmol) was added to a solution of compound
15j (100 mg, 0.107 mmol) and 3-(tributylstannyl)pyridine
(0.059 mg, 0.160 mmol) and in toluene (5 mL) at room tempera-
ture. After stirring at reflux temperature for 18 h, the reaction mix-
ture was cooled to room temperature. The solvent was removed in
vacuo. The residue was purified using silica gel chromatography
(CHCl3/MeOH/NH4OH = 10:1:0.1) to yield compound 15n (33 mg,
34%) as a colorless foam: MASS (ESI) m/z 888.6 [M+H]+; 1H NMR
(CDCl3) d 8.81 (d, J = 1.9 Hz, 1H), 8.55 (dd, J = 4.6, 1.5 Hz, 1H),
7.83 (dt, J = 7.9, 2.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.33 (dd,
J = 7.5, 5.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.69 (d, J = 4.6 Hz, 1H),
4.45 (d, J = 7.3 Hz, 1H), 4.12–4.21 (m, 1H), 3.99–4.07 (m, 5H),
3.68–3.72 (m, 1H), 3.44–3.54 (m, 2H), 3.29 (s, 3H), 3.22 (s, 3H),
3.18–3.21 (m, 1H), 2.96–3.03 (m, 1H), 2.71–2.81 (m, 2H), 2.60–
2.67 (m, 1H), 2.46–2.55 (m, 1H), 2.24–2.43 (m, 12H), 1.81–1.93
(m, 2H), 1.62–1.74 (m, 2H), 1.47–1.55 (m, 2H), 1.19–1.36 (m,
19H), 1.14 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 7.3 Hz, 3H); 13C NMR
(CDCl3) d 176.2, 158.9, 148.0, 147.9, 136.2, 133.9, 130.6, 128.2,
123.5, 115.2, 102.7, 95.4, 80.4, 80.0, 78.8, 78.1, 72.8, 71.0, 70.5,
69.1, 67.1, 65.4, 64.7, 63.1, 60.9, 51.7, 50.0, 49.4, 41.8, 40.4, 37.4,
37.2, 35.2, 32.8, 30.6, 21.7, 21.3, 20.6, 18.1, 14.7, 14.1, 11.3, 10.9;
HRMS (ESI/APCI-dual, [M+H]+) found 888.5596, calcd for C48H77
N3O12 888.5580.
bling
a
yellowish foam. Hydrogen fluoride-pyridine (70%,
89.0 mg, 3.11 mmol) was added to a solution of this 400-O-benzyl-
oxycarbonyl product (1.55 g, 1.56 mmol) in THF (20 mL) at room
temperature. After stirring at room temperature for 18 h, the reac-
tion was neutralized with saturated NaHCO3 (2.0 mL). The result-
ing mixture was diluted with ethyl acetate (10 mL) and then
separated. The organic layer was dried over MgSO4. The solvent
was removed in vacuo to yield compound 17 (1.16 g, 84%), resem-
bling a colorless foam.
Dess–Martin periodinane (818 mg, 1.92 mmol) was added to a
solution of compound 17 (1.13 g, 1.28 mmol) in CH2Cl2 (20 mL)
at room temperature. After stirring at room temperature for
1.0 h, the reaction was quenched with saturated NaHCO3
(2.0 mL). The organic layer was separated and dried over MgSO4.
The solvent was removed in vacuo and the residue was purified
using silica gel chromatography (n-hexane/acetone/Et3N =
10:10:0.2) to yield a 9-keto product, resembling a brownish foam
(810 mg, 72% yield). This material was dissolved in methanol
(5 mL). After stirring at reflux temperature for 1 h, the reaction
mixture was cooled to room temperature. After the addition of
4.1.4.4. Compound 15o.
Compound 15o (27 mg, 28%) was
prepared from compound 15j (100 mg, 0.107 mmol) according to
the procedure used to prepare 15k: ½a D31
ꢀ42.8 (c 0.057, CHCl3);
ꢁ

T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
5797
5% palladium carbon (100 mg), the suspension was stirred in a
hydrogen atmosphere at room temperature. After the removal of
insoluble particles using filtration, the solvent was removed in
vacuo and the residue was purified using silica gel chromatography
(CHCl3/MeOH/NH4OH = 10:1:0.1) to yield compound 19 (280 mg,
to pH 11 with 2 M NaOH solution, and extracted with ethyl acetate
(50 ml ꢂ 2). The organic layer was separated and dried over
MgSO4. The solvent was removed in vacuo and the residue was
purified using silica gel chromatography (CHCl3/MeOH/NH4OH =
20:1:0.1) to yield compound 20 (1.06 g, 32% for two steps) as a
colorless foam: MASS (ESI) m/z 545.3 [M+H]+; 1H NMR (CDCl3) d
3.86–4.50 (m, 4H for both diastereomers and 1H for one diastereo-
mer), 3.18–3.56 (m, 4H for both diastereomers and 1H for one dia-
stereomer), 2.91–2.99 (m, 4H for one diastereomer), 2.85 (s, 3H for
one diastereomer), 2.13–2.76 (m, 14H for both diastereomers and
1H for one diastereomer), 1.59–2.01 (m, 3H for both diastereo-
mers), 1.36 (m, 3H for both diastereomers), 1.16–1.31 (m, 11H
for both diastereomers), 1.00 (d, J = 7.2 Hz, 3H for one diastereo-
mer), 0.86 (d, J = 7.2 Hz, 3H for one diastereomer), 0.83 (d,
J = 6.9 Hz, 3H for one diastereomer), 0.71 (d, J = 6.9 Hz, 3H for one
diastereomer); 13C NMR (CDCl3) d 206.6, 205.9, 172.5, 170.4,
104.8, 104.5, 84.9, 83.2, 81.4, 80.6, 79.0, 77.9, 70.4, 69.8, 69.5,
69.4, 66.4, 65.7, 65.3, 64.3, 61.2, 56.6, 55.7, 54.5, 52.8, 50.3, 50.0,
48.8, 48.1, 45.4, 44.1, 42.9, 42.0, 40.5, 40.3, 37.8, 37.0, 35.8, 34.9,
33.1, 30.7, 29.8, 29.6, 28.5, 21.3, 21.2, 20.2, 17.2, 15.9, 15.2, 14.9,
14.1, 12.3; HRMS (ESI/APCI-dual, [M+H]+) found 545.3806, calcd
for C28H52N2O8 545.3796.
44%) as a colorless foam: ½a D25
ꢀ86.6 (c 0.139, CHCl3); MASS (ESI)
ꢁ
m/z 703.6 [M+H]+; 1H NMR (CDCl3) d 4.78 (d, J = 4.3 Hz, 1H), 4.46
(d, J = 7.3 Hz, 1H), 4.18 (ddd, J = 11.6, 5.5, 2.4 Hz, 1H), 4.01–4.08
(m, 1H), 3.92–3.98 (m, 2H), 3.77 (d, J = 7.3 Hz, 1H), 3.45–3.54 (m,
1H), 3.34 (s, 3H), 3.17–3.25 (m, 4H), 2.98–3.10 (m, 2H), 2.65–2.80
(m, 4H), 2.52–2.59 (m, 1H), 2.41–2.48 (m, 1H), 2.39 (d,
J = 15.3 Hz, 1H), 2.31 (s, 3H), 2.29 (s, 6H), 2.17–2.27 (m, 2H), 2.07
(dd, J = 14.3, 5.8 Hz, 1H), 1.66 (d, J = 13.4 Hz, 1H), 1.56 (dd,
J = 15.3, 4.9 Hz, 1H), 1.48 (dd, J = 15.0, 4.6 Hz, 1H), 1.34 (s, 3H),
1.29 (d, J = 6.7 Hz, 3H), 1.24 (d, J = 6.1 Hz, 6H), 1.06–1.18 (m,
13H); 13C NMR (CDCl3) d 218.2, 176.5, 103.0, 96.0, 79.5, 78.9,
78.2, 72.9, 71.0, 68.9, 65.7, 63.2, 61.6, 56.7, 50.7, 49.5, 44.5, 44.3,
41.8, 41.4, 41.3, 40.8, 40.4, 36.8, 35.0, 28.8, 21.6, 21.5, 20.6, 18.7,
18.4, 16.7, 13.0, 9.6; IR (KBr) 3461, 2974, 1733, 1459, 730 cmꢀ1
HRMS (ESI/APCI-dual, [M+H]+) found 703.4731, calcd for
36H66N2O11 703.4739.
;
C
4.2.2. Synthesis of compound 20
Compound 14a (10.0 g, 9.54 mmol) was dissolved in 1 M aque-
ous hydrochloric acid (50 mL) and EtOH (100 mL) at room temper-
ature. After stirring at 60 °C for 2 h, the EtOH was removed in
vacuo and the residue was washed with ethyl acetate (50 ml ꢂ 2)
and then adjusted to pH 11 with 2 M NaOH solution and extracted
with ethyl acetate (50 ml ꢂ 2). The organic layer was dried over
MgSO4, and removed in vacuo. The residue was used in the next
reaction without further purification. Benzyl chloroformate
(5.02 g, 29.4 mmol) was added to a solution of the residue in
CH2Cl2 (20 mL) and saturated NaHCO3 (40 mL) at 0 °C. After stir-
ring at room temperature for 0.5 h, the reaction was extracted with
CHCl3 (50 mL). The organic layer was separated and dried over
MgSO4. The solvent was removed in vacuo and the residue was
purified using silica gel chromatography (CHCl3/MeOH/NH4OH =
30:1:0.1) to yield compound 18 (4.81 g, 62% for two steps) as a col-
orless foam: MASS (ESI) m/z 815.4 [M+H]+; 1H NMR (CDCl3) d 7.30–
7.41 (m, 10H), 5.13–5.21 (m, 4H), 4.66 (d, J = 7.4 Hz, 1H), 4.56 (dd,
J = 10.3, 7.4 Hz, 1H), 4.50 (d, J = 9.9 Hz, 1H), 4.26–4.31 (m, 1H),
4.00–4.06 (m, 1H), 3.74 (d, J = 2.1 Hz, 1H), 3.41–3.52 (m, 2H),
3.08 (s, 3H), 2.70–2.83 (m, 2H), 2.59–2.66 (m, 1H), 2.45–2.58 (m,
3H), 2.26 (s, 6H), 2.23 (s, 3H), 2.13–2.19 (m, 1H), 2.05–2.13 (m,
1H), 1.97 (d, J = 7.0 Hz, 2H), 1.69–1.74 (m, 1H), 1.30–1.41 (m,
2H), 1.26 (s, 3H), 1.19–1.24 (m, 6H), 1.10 (dd, J = 14.2, 8.5 Hz,
1H), 1.02–1.05 (m, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.75 (d, J = 7.4 Hz,
3H); 13C NMR (CDCl3) d 174.9, 155.8, 154.5, 135.7, 135.5, 128.5,
128.5, 128.4, 128.4, 128.3, 128.1, 100.4, 87.5, 82.7, 78.8, 78.6,
75.7, 69.5, 69.4, 68.9, 63.3, 63.2, 58.8, 56.2, 49.7, 46.2, 44.4, 44.0,
40.7, 36.2, 35.5, 33.8, 30.9, 28.6, 21.2, 21.1, 19.4, 17.1, 14.6, 7.3;
HRMS (ESI/APCI-dual, [M+H]+) found 815.4709, calcd for
4.3. Synthesis of 9-amino derivatives
4.3.1. Synthesis of compound 22
Benzyl chloroformate (66.8 g, 392 mmol) was added to a sus-
pention of compound 21 (131 g, 178 mmol) in CHCl3 (630 mL)
and NaHCO3 (33.8 g, 402 mmol) in distilled water (630 mL) at
0 °C. After stirring at 0 °C for 1.0 h, the reaction was extracted.
The organic layer was washed with brine (500 mL) and dried over
MgSO4. The solvent was removed in vacuo. The residue was recrys-
tallized from diisopropyl ether (1050 mL) to yield 9-N-Cbz, 20-O-
Cbz product (135 g, 75%), resembling a colorless powder. 9-N-Cbz,
20-O-Cbz product (10.0 g, 9.97 mmol) was dissolved in methanol
(50 mL). After stirring at reflux temperature for 18 h, the reaction
mixture was cooling to room temperature. The solvent was re-
moved in vacuo. The residue was dissolved in DMF (50 mL). Chlo-
rotriethylsilane (3.76 g, 24.9 mmol) and imidazole (5.09 g,
74.8 mmol) were added to the solution at room temperature. After
stirring at room temperature for 18 h, the reaction mixture was
diluted with ethyl acetate (50 mL) and n-hexane (50 mL) and
washed with distilled water (200 ml ꢂ 3). The organic layer was
separated and dried over MgSO4. The solvent was removed in vacuo
and the residue was purified using silica gel chromatography (hex-
ane/acetone = 20:1) to yield compound 22 (8.53 g, 78%) as a color-
less foam: 1H NMR (CDCl3) d 7.25–7.37 (m, 5H), 6.06 (d, J = 9.9 Hz,
1H), 5.00–5.16 (m, 3H), 4.66–4.75 (m, 1H), 4.64 (d, J = 9.9 Hz, 1H),
4.06–4.22 (m, 2H), 3.60–3.82 (m, 3H), 3.46 (br s, 1H), 3.32 (s, 3H),
3.29–3.32 (m, 1H), 3.16–3.25 (m, 2H), 2.77–2.84 (m, 1H), 2.46–
2.55 (m, 2H), 2.37 (d, J = 14.9 Hz, 1H), 2.21–2.31 (m, 1H), 2.18 (s,
6H), 2.12–2.16 (m, 1H), 1.88–1.98 (m, 1H), 1.74–1.82 (m, 1H),
1.58–1.71 (m, 2H), 1.43–1.55 (m, 2H), 0.85–1.31 (m, 49H), 0.53–
0.70 (m, 12H); 13C NMR (CDCl3) d 179.1, 157.4, 137.4, 128.5,
128.3, 128.1, 127.7, 101.7, 95.7, 80.9, 77.4, 75.3, 74.7, 73.1, 72.9,
69.5, 67.9, 66.1, 65.9, 65.3, 63.4, 49.0, 45.0, 43.5, 40.9, 35.2, 34.1,
32.1, 29.2, 22.4, 21.6, 21.5, 21.2, 19.2, 18.6, 16.1, 13.9, 12.8, 11.2,
9.7, 7.0, 7.0, 5.5, 5.4, 5.1; IR (KBr) 3526, 2954, 1733, 1511, 1124,
741 cmꢀ1; HRMS (ESI/APCI-dual, [M+H]+) found 1097.7110, calcd
for C57H104N2O14Si2 1097.7099.
C44H66N2O12 815.4689.
Dess–Martin periodinane (3.72 mg, 8.74 mmol) was added to a
solution of compound 18 (4.75 g, 5.83 mmol) in CH2Cl2 (30 mL) at
room temperature. After stirring at room temperature for 1.0 h, the
reaction was quenched with saturated NaHCO3 (20 mL). The organ-
ic layer was separated and dried over MgSO4. The solvent was re-
moved in vacuo and the residue was purified using silica gel
chromatography (CHCl3/MeOH/NH4OH = 30:1:0.1) to yield a crude
3-keto product (5.00 g) as a colorless foam. After the addition of 5%
palladium carbon (1.67 g), the suspension was stirred in a hydro-
gen atmosphere at room temperature for 18 h. After the removal
of the insoluble particles using filtration, the solvent was removed
in vacuo. The residue was dissolved in 1 M aqueous hydrochloric
acid (20 mL) and washed with ethyl acetate (20 mL), then adjusted
4.3.2. Synthesis of compound 23a
Compound 23a (3.0 g, 16%) was prepared from compound 22
(25.0 g, 22.8 mmol) according to the procedure used to prepare
15a: MASS (ESI) m/z 824.4 [M+H]+; 1H NMR (CDCl3) d 7.28–7.40
(m, 5H), 5.76 (br s, 1H), 5.03–5.15 (m, 2H), 4.69 (d, J = 4.3 Hz,

5798
T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
1H), 4.45 (d, J = 7.3 Hz, 1H), 4.19–4.30 (m, 2H), 4.00–4.13 (m, 2H),
3.65–3.71 (m, 1H), 3.48–3.59 (m, 3H), 3.23–3.33 (m, 4H), 2.97–3.05
(m, 1H), 2.76–2.85 (m, 1H), 2.71–2.76 (m, 1H), 2.39–2.55 (m, 3H),
2.28–2.31 (m, 6H), 2.23–2.36 (m, 1H), 2.20 (s, 3H), 1.89–2.17 (m,
4H), 1.71–1.79 (m, 1H), 1.63–1.69 (m, 1H), 1.50 (dd, J = 15.0,
4.6 Hz, 1H), 1.02–1.36 (m, 23H), 0.98 (d, J = 6.7 Hz, 3H); 13C NMR
(CDCl3) d 176.2, 156.8, 137.2, 128.5, 128.2, 128.0, 103.7, 96.4,
85.1, 79.2, 77.9, 75.1, 72.8, 70.9, 69.3, 66.4, 65.9, 65.3, 62.6, 61.8,
59.3, 56.1, 49.4, 45.2, 42.2, 41.3, 40.5, 39.3, 35.1, 33.1, 29.1, 25.6,
21.6, 21.2, 20.0, 18.0, 13.7, 10.1; HRMS (ESI/APCI-dual, [M+H]+)
found 824.5294, calcd for C43H73N3O12 824.5267.
75.2, 73.2, 72.6, 71.0, 70.6, 69.6, 69.3, 65.8, 65.3, 62.6, 59.9, 59.5,
49.4, 45.7, 42.7, 40.4, 39.3, 35.2, 31.4, 29.0, 26.5, 21.6, 21.3, 19.9,
18.8, 18.3, 14.6, 10.2; IR (KBr) 3448, 2973, 1728, 1457, 737 cmꢀ1
;
HRMS (ESI/APCI-dual, [M+H]+) found 810.5493, calcd for C43H75
N3O11 810.5474.
4.4. Synthesis of C12 substituted derivatives
4.4.1. Synthesis of compound 28
A mixture of 14b (25.3 g, 21.7 mmol) and 20% Pd(OH)2 (15.0 g)
in THF (300 mL) was stirred in a hydrogen atmosphere at room
temperature for 72 h. After the removal of the insoluble particles
using filtration, the solvent was removed in vacuo to yield com-
pound 25 (23.3 g, 100%) as a brownish foam: MASS (ESI) m/z
1077.7 [M+H]+; 1H NMR (CDCl3) d 4.81 (d, J = 4.1 Hz, 1H), 4.48–
4.57 (m, 1H), 4.25–4.34 (m, 1H), 3.94–4.13 (m, 3H), 3.67 (d,
J = 5.4 Hz, 1H), 3.58–3.64 (m, 1H), 3.38–3.52 (m, 2H), 3.29 (s, 3H),
3.23 (s, 3H), 3.10–3.26 (m, 3H), 2.80–2.88 (m, 1H), 2.60–2.77 (m,
3H), 2.44–2.53 (m, 1H), 2.31 (d, J = 14.9 Hz, 1H), 2.19 (br s, 9H),
2.03–2.09 (m, 1H), 1.83–1.95 (m, 2H), 1.60–1.67 (m, 1H), 1.45–
1.52 (m, 2H), 1.27 (s, 3H), 1.23 (d, J = 6.6 Hz, 3H), 1.05–1.21 (m,
14H), 0.87–1.00 (m, 33H), 0.54–0.69 (m, 18H); 13C NMR (CDCl3) d
176.1, 125.5, 102.0, 95.6, 81.0, 80.2, 77.8, 73.5, 73.1, 67.7, 65.9,
65.2, 64.7, 61.8, 58.3, 50.0, 49.5, 44.6, 41.0, 40.2, 39.2, 36.0, 32.0,
30.3, 29.4, 29.3, 22.3, 21.9, 19.9, 18.8, 13.5, 12.6, 11.3, 7.1, 7.1,
7.0, 5.5, 5.5, 5.3, 5.2; HRMS (ESI/APCI-dual, [M+H]+) found
1077.7609, calcd for C55H112N2O12Si3 1077.7596.
4.3.3. Synthesis of compound 23e
Compound 23e (1.39 g, 16%) was prepared from compound 22
(10.0 g, 9.11 mmol) according to the procedure used to prepare
15a: MASS (ESI/APCI-dual) m/z 944.6 [M+H]+; 1H NMR (CDCl3) d
7.27–7.38 (m, 10H), 5.80–5.90 (m, 1H), 5.22–5.28 (m, 1H), 5.10
(d, J = 12.4 Hz, 1H), 5.00–5.05 (m, 1H), 4.71–4.76 (m, 1H), 4.43–
4.56 (m, 3H), 4.24–4.29 (m, 1H), 3.98–4.06 (m, 1H), 3.84–3.92
(m, 1H), 3.57–3.70 (m, 2H), 3.48–3.56 (m, 1H), 3.44 (d, J = 5.0 Hz,
1H), 3.33–3.37 (m, 1H), 3.27–3.30 (m, 1H), 3.26 (s, 3H), 2.90–3.01
(m, 2H), 2.82–2.89 (m, 1H), 2.75–2.82 (m, 1H), 2.44–2.53 (m,
1H), 2.20–2.42 (m, 11H), 2.18 (s, 3H), 2.07–2.13 (m, 1H), 1.85–
2.02 (m, 3H), 1.61–1.68 (m, 1H), 1.32–1.45 (m, 2H), 1.16–1.30
(m, 13H), 1.04–1.15 (m, 9H), 0.97 (d, J = 6.6 Hz, 3H); 13C NMR
(CDCl3) d 174.0, 156.7, 138.0, 137.1, 128.4, 128.2, 127.9, 127.7,
127.5, 103.7, 96.7, 84.3, 79.9, 77.7, 77.3, 77.0, 76.8, 75.2, 73.2,
72.6, 70.9, 70.5, 69.6, 69.3, 66.3, 66.1, 65.2, 63.3, 60.3, 59.7, 49.3,
46.1, 40.9, 40.4, 39.9, 35.3, 31.9, 29.1, 26.2, 21.6, 21.2, 20.5, 19.6,
18.1, 14.4, 10.2; HRMS (ESI/APCI-dual, [M+H]+) found 944.5873,
calcd for C51H81N3O13 944.5842.
DBU (510 mg, 3.35 mmol) was added to a solution of compound
25 (3.01 g, 2.79 mmol) and bis(p-nitrophenyl)phosphorazidate
(1.78 g, 5.59 mmol) in toluene (30 mL) at room temperature. After
stirring at 50 °C for 3.0 h, the solvent was removed in vacuo and
the residue was purified using silica gel chromatography (n-hex-
ane/acetone/Et3N = 50:1:0.1) to yield crude compound 26 (2.86 g)
4.3.4. Synthesis of compound 24a
A mixture of 23a (3.0 g, 3.64 mmol) and 5% palladium carbon
(1.0 g) was stirred in a hydrogen atmosphere at room temperature
for 18 h. After the removal of the insoluble particles using filtra-
tion, the solvent was removed in vacuo and the residue was puri-
fied using silica gel chromatography (CHCl3/MeOH/NH4OH =
10:1:0.1) to yield compound 24a (1.20 g, 48%) as a colorless foam:
as a yellow foam. Hydrogen fluoride-pyridine (70%, 371 mg,
13.0 mmol) was added to a solution of compound 26 (2.86 g,
2.59 mmol) in THF (5.0 mL) at room temperature. After stirring at
room temperature for 18 h, the reaction was neutralized with sat-
urated NaHCO3 (20 mL). The resulting mixture was diluted with
ethyl acetate (20 mL) and then separated. The organic layer was
dried over MgSO4. The solvent was removed in vacuo and the res-
idue was purified using silica gel chromatography (CHCl3/MeOH/
NH4OH = 10:1:0.1) to yield compound 27 (1.89 g, 89% for two
steps) as a colorless foam: HRMS (ESI/APCI-dual, [M+H]+) found
760.5077, calcd for C37H69N5O11 760.5066.
½
a 2D6
ꢁ
ꢀ59.0 (c 0.248, CHCl3); MASS (ESI) m/z 690.3 [M+H]+; 1H NMR
(CDCl3) d 4.77 (d, J = 4.9 Hz, 1H), 4.43 (d, J = 6.7 Hz, 1H), 4.24 (dd,
J = 6.1, 1.8 Hz, 1H), 4.13–4.18 (m, 2H), 4.03–4.09 (m, 1H), 3.50–
3.60 (m, 3H), 3.31 (s, 3H), 3.27 (dd, J = 9.8, 7.3 Hz, 1H), 3.02
(t, J = 9.8 Hz, 1H), 2.70–2.90 (m, 3H), 2.30 (s, 6H), 2.26 (s, 3H),
2.05–2.54 (m, 6H), 1.82–1.89 (m, 1H), 1.61–1.70 (m, 2H), 1.57
(dd, J = 15.3, 4.9 Hz, 1H), 1.40 (dd, J = 14.6, 5.5 Hz, 1H), 1.31 (d,
J = 6.1 Hz, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.19 (d, J = 7.3 Hz, 3H),
1.12–1.25 (m, 4H), 1.06–1.11 (m, 6H), 0.99 (d, J = 7.3 Hz, 3H); 13C
NMR (CDCl3) d 175.7, 103.3, 95.5, 84.7, 79.2, 78.0, 74.9, 72.8,
71.0, 69.1, 65.6, 65.4, 62.1, 61.6, 59.8, 56.3, 49.4, 44.3, 42.5, 40.6,
40.4, 35.0, 30.9, 28.9, 26.1, 21.6, 21.3, 20.0, 18.9, 18.1, 13.8, 10.0;
IR (KBr) 3444, 2976, 1734, 1460 cmꢀ1; HRMS (ESI/APCI-dual,
[M+H]+) found 690.4913, calcd for C35H67N3O10 690.4899.
Triphenylphosphine (5.95 g, 22.7 mmol) was added to a solu-
tion of compound 27 (20.4 g, 18.9 mmol) and distilled water
(408 mg, 22.7 mmol) in THF (200 mL) at room temperature. After
stirring at room temperature for 24 h, the solvent was removed
in vacuo and the residue was purified using silica gel chromatogra-
phy (CHCl3/MeOH/NH4OH = 10:1:0.1) to yield compound 28
(10.4 g, 53%) as a colorless foam: ½a D31
ꢀ49.7 (c 0.193, CHCl3); MASS
ꢁ
(ESI) m/z 734.5 [M+H]+; 1H NMR (CDCl3) d 4.84 (d, J = 4.2 Hz, 1H),
4.47 (d, J = 7.2 Hz, 1H), 4.23–4.29 (m, 1H), 4.18 (m, J = 9.9 Hz,
1H), 4.04–4.11 (m, 1H), 3.98 (dd, J = 11.7, 7.8 Hz, 1H), 3.80 (d,
J = 6.8 Hz, 1H), 3.44–3.58 (m, 2H), 3.32 (s, 3H), 3.25 (s, 3H), 3.18–
3.23 (m, 1H), 3.01 (d, J = 9.5 Hz, 1H), 2.95 (dd, J = 7.3, 3.0 Hz, 1H),
2.77–2.92 (m, 3H), 2.43–2.67 (m, 3H), 2.31 (s, 6H), 2.26–2.38 (m,
1H), 2.22 (s, 3H), 1.93–2.15 (m, 3H), 1.78–1.88 (m, 1H), 1.65–
1.73 (m, 1H), 1.55 (dd, J = 15.1, 4.9 Hz, 1H), 1.34 (s, 3H), 1.28 (d,
J = 6.4 Hz, 3H), 1.23 (s, 3H), 1.19 (d, J = 7.3 Hz, 3H), 1.13–1.26 (m,
5H), 1.10 (d, J = 7.3 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 0.89 (d,
J = 6.8 Hz, 3H); 13C NMR (CDCl3) d 175.9, 103.4, 95.7, 80.8, 80.0,
79.0, 78.6, 78.1, 72.8, 70.9, 69.0, 66.1, 65.5, 65.4, 62.8, 50.3, 49.5,
44.2, 40.4, 40.1, 39.7, 37.2, 35.2, 34.3, 33.6, 32.1, 29.0, 21.7, 21.4,
20.9, 18.1, 16.4, 13.0, 11.5; HRMS (ESI/APCI-dual, [M+H]+) found
734.5188, calcd for C37H71N3O11 734.5161.
4.3.5. Synthesis of compound 24e
Compound 24e (810 mg, 68%) was prepared from compound
23e (2.40 g, 1.47 mmol) according to the procedure used to prepare
24a: ½a 2D5
ꢁ
ꢀ35.0 (c 0.221, CHCl3); MASS (ESI) m/z 811.5 [M+H]+; 1H
NMR (CDCl3) d 7.25–7.38 (m, 5H), 4.74 (m, 1H), 4.43–4.54 (m, 3H),
4.14–4.24 (m, 3H), 4.04 (m, 1H), 3.50–3.63 (m, 3H), 3.45 (m, 1H),
3.31 (s, 3H), 3.14–3.35 (m, 2H), 3.02 (m, 1H), 2.67–2.82 (m, 3H),
2.42–2.56 (m, 2H), 2.29 (s, 6H), 2.23 (s, 3H), 2.06–2.37 (m, 4H),
1.74–1.88 (m, 2H), 1.66 (m, 1H), 1.55 (dd, J = 15.23, 4.82 Hz, 1H),
1.30 (d, J = 6.22 Hz, 3H), 1.23 (s, 3H), 1.21 (s, 3H), 1.15–1.31 (m,
8H), 1.05 (m, 6H), 0.95 (d, J = 6.84 Hz, 3H); 13C NMR (CDCl3) d
174.2, 137.9, 128.4, 127.7, 127.6, 103.8, 96.2, 84.3, 80.1, 78.0,

T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
5799
4.4.2. General procedure for the synthesis of compounds 29, 31,
32
4.4.3. Synthesis of compound 30
Sodium triacetoxyborohydride (132 mg, 0.625 mmol) was
added to a solution of compound 28 (90 mg, 0.125 mmol) and acet-
aldehyde (5.5 mg, 0.125 mmol) in CH2Cl2 (1.0 mL). After stirring at
room temperature for 0.5 h, nicotine aldehyde (20 mg,
0.189 mmol) was added to the reaction and stirred for 0.5 h. The
reaction was quenched by adding saturated NaHCO3 (5 mL), and
the aqueous layer was extracted with CHCl3 (5 mL). The combined
organic layer was dried over MgSO4. The solvent was removed in
vacuo, and the residue was purified using silica gel chromatogra-
phy (CHCl3/MeOH/NH4OH = 10:1:0.1) to yield compound 30
Sodium triacetoxyborohydride (132 mg, 0.625 mmol) was
added to a solution of compound 28 (90 mg, 0.125 mmol) and acet-
aldehyde (28 mg, 0.625 mmol) in CH2Cl2 (1.0 mL). After stirring at
room temperature for 1 h, the reaction was quenched by adding
saturated NaHCO3 (5 mL), and the aqueous layer was extracted
using CHCl3 (5 mL). The combined organic layer was dried over
MgSO4. The solvent was removed in vacuo, and the residue was
purified using silica gel chromatography (CHCl3/MeOH/NH4OH =
10:1:0.1) to yield compound 29 (14 mg, 14%) as a colorless foam:
½
a 2D5
ꢁ
ꢀ31.0 (c 0.125, CHCl3); MASS (ESI) m/z 790.4 [M+H]+; 1H
(36 mg, 35%) as a colorless foam: ½a D25
ꢀ36.1 (c 0.398, CHCl3);
ꢁ
NMR (CDCl3) d 4.86 (m, J = 3.9 Hz, 1H), 4.45 (d, J = 7.3 Hz, 1H),
4.39 (dd, J = 11.7, 2.8 Hz, 1H), 4.04–4.15 (m, 1H), 3.95 (dd,
J = 11.7, 7.9 Hz, 1H), 3.83 (d, J = 7.3 Hz, 1H), 3.42–3.63 (m, 3H),
3.31 (s, 3H), 3.22 (s, 3H), 3.19–3.26 (m, 1H), 2.68–3.04 (m, 4H),
2.30 (s, 6H), 2.24 (s, 3H), 2.05–2.62 (m, 11H), 1.91–2.03 (m, 1H),
1.62–1.83 (m, 2H), 1.52 (dd, J = 14.9, 5.0 Hz, 1H), 1.33 (s, 3H),
1.28 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 7.3 Hz, 3H), 1.09–1.26 (m,
14H), 0.87–1.02 (m, 9H), 0.80 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3)
d 176.5, 103.9, 96.5, 80.8, 80.2, 78.6, 78.3, 78.1, 72.8, 70.9, 69.1,
65.6, 65.3, 63.0, 62.7, 50.1, 49.9, 49.5, 47.5, 46.5, 45.0, 44.2, 40.8,
40.4, 37.3, 35.4, 35.3, 34.0, 31.3, 29.3, 21.7, 21.4, 19.8, 18.1, 16.3,
14.5, 12.4, 11.7; HRMS (ESI/APCI-dual, [M+H]+) found 790.5787,
calcd for C41H79N3O11 790.5787.
MASS (ESI) m/z 853.4 [M+H]+; 1H NMR (CDCl3) d 8.47–8.53 (m,
2H), 7.65–7.73 (m, 1H), 7.22–7.28 (m, 1H), 4.84–4.89 (m, 1H),
4.34–4.47 (m, 3H), 4.03–4.14 (m, 1H), 3.78–3.87 (m, 2H), 3.39–
3.71 (m, 5H), 3.31 (s, 3H), 3.20–3.26 (m, 1H), 3.19 (s, 3H), 2.89–
3.09 (m, 3H), 2.28 (s, 6H), 2.19 (s, 3H), 1.89–2.66 (m, 11H), 1.59–
1.84 (m, 2H), 1.53 (dd, J = 15.0, 4.7 Hz, 1H), 1.32 (s, 3H), 1.28 (d,
J = 6.4 Hz, 3H), 1.22 (s, 3H), 1.18 (d, J = 7.5 Hz, 3H), 1.11 (d,
J = 7.0 Hz, 3H), 0.98–1.31 (m, 8H), 0.91 (d, J = 7.5 Hz, 3H), 0.82 (d,
J = 6.7 Hz, 3H); 13C NMR (CDCl3) d 176.4, 150.1, 148.5, 136.5,
134.9, 123.4, 103.7, 96.4, 80.7, 80.3, 78.7, 78.1, 72.8, 70.9, 69.0,
65.7, 65.3, 62.9, 62.8, 62.0, 56.1, 54.7, 50.6, 50.0, 49.5, 47.7, 44.8,
40.4, 37.2, 35.2, 34.8, 34.2, 34.1, 31.5, 30.4, 29.3, 21.7, 21.3, 21.3,
18.1, 16.8, 15.6, 12.7, 11.6, 11.0; HRMS (ESI/APCI-dual, [M+H]+)
found 853.5888, calcd for C45H80N4O11 853.5896.
4.4.2.1. Compound 31.
The general procedure used for com-
pound 28 (90 mg, 0.125 mmol) was also used for compound 31
4.5. Synthesis of 400-carbamate derivatives
(22 mg, 20%), which resembled as a colorless foam: ½a D25
ꢀ29.2
ꢁ
(c 0.200, CHCl3); MASS (ESI) m/z 916.5 [M+H]+; 1H NMR (CDCl3) d
8.54 (d, J = 2.0 Hz, 2H), 8.52 (dd, J = 4.8, 1.5 Hz, 2H), 7.69–7.74 (m,
2H), 7.25–7.30 (m, 2H), 4.91 (m, J = 4.3 Hz, 1H), 4.41–4.47 (m,
2H), 4.29–4.35 (m, 1H), 4.22 (dd, J = 5.9, 3.7 Hz, 1H), 4.02–4.12
(m, 1H), 3.57–3.85 (m, 4H), 3.38–3.54 (m, 5H), 3.32 (s, 3H), 3.16
(s, 3H), 2.89–3.24 (m, 4H), 2.27 (s, 6H), 2.15–2.65 (m, 7H), 2.07 (s,
3H), 1.88–2.05 (m, 2H), 1.58–1.79 (m, 2H), 1.54 (dd, J = 15.1,
4.8 Hz, 1H), 1.31 (s, 3H), 1.27 (d, J = 6.1 Hz, 3H), 1.23 (s, 3H), 1.19
(d, J = 7.3 Hz, 3H), 1.10 (d, J = 7.2 Hz, 3H), 1.07–1.34 (m, 5H), 0.82–
0.95 (m, 6H); 13C NMR (CDCl3) d 176.3, 150.3, 148.9, 136.7, 134.0,
130.9, 128.8, 123.5, 103.5, 96.2, 80.5, 80.1, 78.8, 78.1, 77.8, 72.8,
70.9, 69.0, 68.2, 65.6, 65.4, 62.7, 61.6, 56.2, 51.1, 50.2, 49.5, 44.7,
40.5, 40.4, 38.8, 37.1, 35.2, 34.7, 34.3, 30.4, 29.1, 28.9, 23.8, 23.0,
21.7, 21.3, 21.2, 18.2, 14.1, 13.0, 11.4, 11.0; HRMS (ESI/APCI-dual,
[M+H]+) found 916.6002, calcd for C49H81N5O11 916.6005.
4.5.1. Synthesis of compound 33a/e
Acetic anhydride (67 mg, 0.657 mmol) was added to a solution
of compound 23a (190 mg, 0.219 mmol) in acetone (5 mL) at room
temperature. After stirring at room temperature for 6 h, the reac-
tion was diluted with ethyl acetate (10 mL) and saturated NaHCO3
(5 mL). The organic layer was separated and dried over MgSO4. The
solvent was removed in vacuo to yield crude 20-O-acetyl product
resembling a colorless foam. 1,10-Carbonyldiimidazole (107 mg,
0.657 mmol) was added to a suspension of the crude 20-O-acetyl
product in THF (5 mL)-DMF (1 mL) at room temperature. After stir-
ring at room temperature for 2 h, the reaction was diluted with
ethyl acetate (10 mL) and saturated NH4Cl (5 mL). The organic
layer was separated and dried over MgSO4. The solvent was re-
moved in vacuo and the residue was purified using silica gel chro-
matography
(n-hexane/acetone/Et3N = 10:10:0.2)
to
yield
compound 33a (189 mg, 90%) as a colorless foam: 1H NMR (CDCl3)
d 8.08 (s, 1H), 7.27–7.40 (m, 5H), 7.11 (s, 1H), 5.50 (br s, 1H), 5.05–
5.13 (m, 2H), 4.80–4.85 (m, 1H), 4.71–4.79 (m, 3H), 4.41–4.50 (m,
1H), 4.20–4.30 (m, 2H), 3.99–4.06 (m, 1H), 3.82 (br s, 1H), 3.57–
3.70 (m, 2H), 3.53 (d, J = 5.8 Hz, 1H), 3.38 (s, 3H), 2.69–2.88 (m,
3H), 2.39–2.50 (m, 4H), 2.29 (s, 3H), 2.19 (s, 3H), 2.01–2.09 (m,
7H), 1.94–2.00 (m, 1H), 1.85–1.92 (m, 1H), 1.59–1.78 (m, 3H),
1.25–1.40 (m, 2H), 1.03–1.23 (m, 18H), 0.93–1.00 (m, 6H); 13C
NMR (CDCl3) d 175.9, 169.8, 156.7, 148.7, 136.9, 130.9, 128.4,
128.2, 128.0, 117.0, 100.1, 95.7, 83.2, 83.0, 78.8, 77.2, 75.1, 72.8,
71.7, 68.3, 66.4, 63.4, 62.8, 62.4, 61.8, 59.3, 56.4, 49.4, 46.1, 44.2,
42.1, 41.4, 40.7, 38.8, 35.3, 33.3, 30.7, 29.3, 25.1, 21.4, 21.3, 21.1,
19.6, 17.6, 13.4, 9.7; HRMS (ESI/APCI-dual, [M+H]+) found
960.5546, calcd for C49H77N5O14 960.5540.
Compound 33e (304 mg, 83% for two steps) was prepared from
compound 23e (325 mg, 0.344 mmol) according to the procedure
used to prepare 33a: MASS (ESI) m/z 1080.7 [M+H]+; 1H NMR
(CDCl3) d 8.09 (s, 1H), 7.25–7.41 (m, 11H), 7.11 (s, 1H), 5.82–5.90
(m, 1H), 5.21–5.27 (m, 1H), 5.02–5.09 (m, 2H), 4.80–4.85 (m, 2H),
4.74 (d, J = 7.4 Hz, 1H), 4.70 (d, J = 9.9 Hz, 1H), 4.38–4.54 (m, 3H),
4.22 (d, J = 5.8 Hz, 1H), 3.42–3.67 (m, 5H), 3.32 (s, 3H), 2.92 (d,
4.4.2.2. Compound 32.
The general procedure used for com-
pound 28 (100 mg, 0.136 mmol) was also used for compound 32
(55 mg, 36%), which resembled a colorless foam: ½a D25
ꢀ34.1 (c
ꢁ
0.042, CHCl3); MASS (ESI) m/z 1104.7 [M+H]+; 1H NMR (CDCl3) d
8.70 (d, J = 2.2 Hz, 2H), 8.51 (d, J = 2.0 Hz, 2H), 7.94 (t, J = 1.8 Hz,
2H), 7.51–7.59 (m, 4H), 7.14 (t, J = 8.6 Hz, 4H), 4.85 (d, J = 4.2 Hz,
1H), 4.57 (dd, J = 11.6, 1.9 Hz, 1H), 4.43 (d, J = 7.3 Hz, 1H), 4.18–
4.26 (m, 1H), 3.98–4.07 (m, 1H), 3.85 (d, J = 14.8 Hz, 2H), 3.76
(d, J = 6.2 Hz, 1H), 3.58–3.67 (m, 1H), 3.52 (d, J = 13.7 Hz, 2H),
3.35–3.48 (m, 2H), 3.28 (s, 3H), 3.13–3.24 (m, 2H), 3.11 (s, 3H),
2.83–3.02 (m, 2H), 2.31 (s, 6H), 2.11 (s, 3H), 1.89–2.74 (m, 8H),
1.42–1.75 (m, 4H), 1.28 (s, 3H), 1.22 (d, J = 6.5 Hz, 3H), 1.19 (s, 3H),
1.17 (d, J = 7.2 Hz, 3H), 1.12–1.26 (m, 5H), 1.07 (d, J = 7.3 Hz, 1H),
0.92 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3) d
176.6, 164.0, 162.0, 148.9, 147.2, 135.5, 134.9, 134.2, 133.6, 128.9,
128.8, 116.2, 116.0, 103.3, 95.7, 80.4, 79.9, 78.6, 78.0, 77.6, 72.7,
70.9, 68.9, 65.6, 65.4, 62.8, 56.1, 51.3, 50.3, 49.4, 44.6, 40.6, 40.3,
35.0, 35.0, 29.0, 21.6, 21.4, 21.1, 18.2, 13.5, 10.9; IR (KBr) 3437,
2973, 1728, 1608, 1515, 836, 724 cmꢀ1; HRMS (ESI/APCI-dual,
[M+H]+) found 1104.6442, calcd for C61H87F2N5O11 1104.6443.

5800
T. Sugimoto et al. / Bioorg. Med. Chem. 20 (2012) 5787–5801
J = 12.0 Hz, 1H), 2.78–2.84 (m, 1H), 2.69–2.76 (m, 1H), 2.33–2.44
(m, 2H), 2.29 (s, 6H), 2.27 (d, J = 6.6 Hz, 1H), 2.13–2.19 (m, 3H),
2.01–2.10 (m, 5H), 1.92 (d, J = 6.6 Hz, 1H), 1.79–1.85 (m, 1H), 1.74
(d, J = 12.4 Hz, 1H), 1.53 (d, J = 14.4 Hz, 1H), 1.26–1.42 (m, 3H),
1.16–1.22 (m, 3H), 0.95–1.15 (m, 21H); 13C NMR (CDCl3) d 173.9,
169.8, 156.6, 148.7, 138.0, 137.1, 137.0, 131.0, 128.4, 128.4, 128.4,
127.9, 127.8, 127.5, 117.0, 100.2, 96.0, 83.0, 82.7, 75.1, 73.3, 72.7,
71.7, 70.4, 69.7, 68.4, 66.4, 63.2, 62.8, 60.2, 59.7, 49.3, 45.8, 40.7,
40.0, 38.7, 35.3, 31.7, 30.7, 25.4, 21.4, 21.3, 21.0, 20.1, 19.5, 17.7,
14.6, 9.9; HRMS (ESI/APCI-dual, [M+H]+) found 1080.6130, calcd
for C57H85N5O15 1080.6115.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2012.08.007.
References and notes
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Academic Press, 2002.
2. Kaneko, T.; Dougherty, T. J.; Magee, T. V. Macrolide Antibiotics In
Comprehensive Medicinal Chemistry II; Taylor, J. B., Triggle, D. J., Eds.; Elsevier
Ltd: Oxford, UK, 2006; Vol. 7, p 973.
3. Blondeau, J. M. Expert Opin. Pharmacother. 2002, 3, 1131.
4. Blondeau, J. M.; DeCarolis, E.; Metzer, K. L.; Hansen, G. T. Expert Opin. Investig.
Drugs 2002, 11, 189.
4.5.2. Synthesis of compound 35a
5. Kurath, P.; Jones, P. H.; Egan, R. S.; Perun, T. J. Experientia 1971, 27, 362.
6. Wilson, J. T.; van Boxtel, C. J. Antibiot. Chemother. 1978, 25, 181.
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A mixture of 33a (90 mg, 0.094 mmol) and amine 34 (17 mg,
0.077) was stirred at room temperature for 6 days. The solvent
was removed in vacuo and the residue was purified using silica
gel chromatography (n-hexane/acetone/Et3N = 10:10:0.2) to yield
a crude carbamate product resembling a colorless foam. This
material was dissolved in methanol (5 mL). After stirring at reflux
temperature for 1 h, the reaction mixture was cooling to room
temperature. After the addition of 5% palladium carbon (50 mg),
the suspension was stirred in a hydrogen atmosphere at room
temperature for 18 h. After the removal of the insoluble particles
using filtration, the solvent was removed in vacuo and the residue
was purified using silica gel chromatography (CHCl3/MeOH/
NH4OH = 10:1:0.1) to yield compound 35a (20 mg, 23% for two
ˇ
8. Djokic´, S.; Kobrehel, G.; Lazarevski, G.; Lopotar, N.; Tamburase v, Z. J. Chem. Soc.,
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M.; Ewing, P.; Alder, J.; Ma, Z. J. Med. Chem. 2000, 43, 1045.
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X.; Zhong, P.; Cao, Z.; Nilius, A. M.; Shortridge, V. D.; Flamm, R.; Mitten, M.;
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steps) as a colorless foam: ½a D31
ꢀ72.6 (c 0.357, CHCl3); MASS
ꢁ
(ESI) m/z 938.9 [M+H]+; 1H NMR (CDCl3) d 7.20–7.46 (m, 2H),
6.93–6.99 (m, 1H), 6.90 (d, J = 8.6 Hz, 1H), 4.85 (d, J = 4.3 Hz,
1H), 4.52–4.58 (m, 1H), 3.99–4.51 (m, 4H), 3.85 (s, 3H), 3.28 (s,
3H), 2.92–3.70 (m, 7H), 2.39 (s, 6H), 2.37 (s, 3H), 2.16–2.90 (m,
14H), 1.33 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.15 (s, 3H), 1.04 (d,
J = 6.7 Hz, 3H), 0.86–2.15 (m, 24H); 13C NMR (CDCl3) d 175.8,
157.2, 156.5, 131.6, 127.9, 127.7, 120.3, 110.6, 102.8, 96.1, 84.2,
78.9, 74.9, 73.2, 71.1, 68.4, 65.2, 63.5, 61.8, 61.5, 59.9, 56.4,
55.3, 51.0, 49.4, 48.9, 44.5, 42.8, 42.6, 40.7, 40.4, 38.9, 38.4,
35.6, 34.4, 30.8, 29.0, 26.2, 21.6, 21.0, 20.0, 18.9, 17.7, 16.7,
13.7, 12.6, 10.1; HRMS (ESI/APCI-dual, [M+H]+) found 938.6417,
calcd for C49H87N5O12 938.6424.
22. Tennakoon, M. A.; Henninger, T. C.; Abbanat, D.; Foleno, B. D.; Hilliard, J. J.;
Bush, K.; Macielag, M. Bioorg. Med. Chem. Lett. 2006, 16, 6231.
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4.5.3. Synthesis of compound 35e
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(106 mg, 0.0859 mmol) according to the procedure used to prepare
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35a. Compound 35e : ½a D31
ꢁ
ꢀ26.3 (c 0.160, CHCl3); 1H NMR (CDCl3)
d 7.25–7.37 (m, 6H), 7.18–7.23 (m, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.87
(d, J = 7.9 Hz, 1H), 5.57 (t, J = 4.6 Hz, 1H), 5.23–5.30 (m, 1H), 4.87 (d,
J = 4.8 Hz, 1H), 4.44–4.55 (m, 5H), 4.34–4.42 (m, 4H), 3.84 (s, 3H),
3.63–3.69 (m, 2H), 3.54–3.60 (m, 1H), 3.47–3.52 (m, 2H), 3.38 (br
s, 1H), 3.29 (s, 3H), 3.21–3.27 (m, 3H), 2.91–2.99 (m, 1H), 2.82–
2.89 (m, 1H), 2.46–2.66 (m, 6H), 2.31–2.46 (m, 4H), 2.15–2.30
(m, 11H), 2.02–2.10 (m, 1H), 1.92–2.01 (m, 1H), 1.84–1.91 (m,
1H), 1.65–1.72 (m, 1H), 1.48–1.59 (m, 2H), 1.33–1.40 (m, 1H),
1.06–1.32 (m, 19H), 1.03 (d, J = 6.5 Hz, 3H), 0.90–0.99 (m, 6H);
13C NMR (CDCl3) d 157.2, 156.5, 137.9, 131.3, 128.4, 127.8, 127.7,
127.6, 120.2, 110.6, 103.6, 78.9, 75.1, 73.2, 70.9, 70.6, 69.6, 68.8,
65.1, 63.5, 62.7, 59.9, 55.3, 51.4, 49.5, 49.2, 45.7, 43.1, 40.3, 39.4,
35.7, 31.3, 29.0, 26.9, 21.4, 21.0, 20.1, 18.6, 17.7, 16.4, 14.2, 13.2,
10.4; HRMS (ESI/APCI-dual, [M+H]+) found 1058.6998, calcd for
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The minimal inhibitory concentration (MIC) was determined
using the broth microdilution method according to the Clinical
and Laboratory Standards Institute’s guidelines for S. pnuemoniae.

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