Novel antibacterial macrolides: Synthesis of 15-membered diolides

Article abstract of DOI:10.1021/jo020458e

Novel 15-membered macrolides possessing the dilactone skeleton, diolides 13a and 13b, have been synthesized in our research program aimed at finding new antibacterial macrolides. Key strategic elements of the approach include the ring-expanding reaction o

Full text of DOI:10.1021/jo020458e

Novel An tiba cter ia l Ma cr olid es: Syn th esis of 15-Mem ber ed
Diolid es
Takafumi Ohara, Masaharu Kume,* Yukitoshi Narukawa, Kiyoshi Motokawa,
Kouichi Uotani, and Hiroshi Nakai
Discovery Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, J apan
masaharu.kume@shionogi.co.jp
Received J uly 9, 2002
Novel 15-membered macrolides possessing the dilactone skeleton, diolides 13a and 13b, have been
synthesized in our research program aimed at finding new antibacterial macrolides. Key strategic
elements of the approach include the ring-expanding reaction of 13-membered dilactones, prepared
from erythromycin A (Ery-A), to 15-membered dilactones via intramolecular translactonization.
The absolute configuration at the regenerated C-8 position of the new diolides was determined by
chemical transformation, leading to the corresponding lactam analogues, whose stereochemistry
is known in the literature. For further confirmation, X-ray analysis was performed. The X-ray
structure determination of 13a revealed a backbone conformation similar to that of Ery-A. Novel
15-membered diolide 13a and the 11,12-diol 18 exhibited antibacterial activities comparable to
that of Ery-A.
In tr od u ction
macrolide antibiotics having novel characteristics. The
chemistry performed on Ery-A in the past can be divided
into two main categories: (1) modification of peripheral
substituents on the macrolide nucleus and (2) transfor-
mation affecting the aglycon scaffold, which is expected
to lead to significant biological improvements. From a
synthetic point of view, the latter approach is considered
to be more challenging4 but often results in decrease or
loss of antibacterial potency. Only a limited number of
such approaches were successful, exemplified by the
azalides (e.g., azithromycin, 2).5 In the course of our
exploratory investigation on macrolides, we were at-
tracted to this latter approach and set out to find a route
to a new nucleus. This led us to try modifications of the
framework of erythromycin derivatives. Our efforts led
to the establishment of a synthetic route to a novel 15-
membered diolide. Here we report the synthesis of new
diolides that demonstrate antibacterial activities com-
parable to that of Ery-A.
The erythromycin family consists of an important
antibiotics known for some 50 years. Erythromycin A
(Ery-A, 1) has provided effective and, above all, safe
antibiotic therapy for much of that time. However, it
undergoes decomposition within the acidic medium of the
stomach, which results in poor oral bioavailability and
undesired gastrointestinal side effects.1 In the past
decade, a number of new semisynthetic erythromycin
derivatives have been synthesized by structural modifi-
cations. They addressed the above shortcomings and
offered better biological and pharmacodynamic properties
than the parent Ery-A.2,3
Resu lts a n d Discu ssion
P la n n n in g. Our strategy for synthesizing the 15-
membered diolide 5 was planned to involve a ring-
(3) Morimoto, S.; Takahashi, Y.; Adachi, T.; Nagate, T.; Watanabe,
Y.; Omura, S. J . Antibiot. 1990, 43, 286.
Structural modification of Ery-A is still considered to
be one of the most effective approaches for producing
(4) For example, see: (a) 11-membered analogues: Kirst, H. A.;
Wind, J . A.; Paschal. J . W. J . Org. Chem. 1987, 52, 4359. (b)
12-Membered analogues: Kibwage, I. O.; Busson, R.; J anssen, G.;
Hoogmartens, J .; Vanderhaeghe H.; Brache J . J . Org. Chem. 1987,
52, 990. (c) 13-Membered analogues: Burnell-Curty, C.; Faghih, R.;
Pagano, T.; Henry, R. F.; Lartey, P. A. J . Org. Chem. 1996, 61, 5153.
(d) 14-Membered azalide: J ones, A. B. J . Org. Chem. 1992, 57, 4361.
(5) Bright, G. M.; Nagel, A. A.; Bordner, J .; Desai, K. A.; Dibrino, J .
N.; Nowakowska, J .; Vincent, L.; Watrous, R. W.; Sciavolino, F. C.;
English. A. R.; Retsema, J . A.; Anderson. M. R.; Brennan, L. A.;
Borovoy, R. J .; Cimochowaski, C. R.; Faiella, J . A.; Girard, D.; Herbert,
C.; Manousos, M.; Mason, R. J . Antibiot. 1988, 41, 1029.
* Corresponding author. Phone: +81-6-6458-5861. Fax: +81-6-
6458-0987.
(1) Kurath, P.; J ones, P. H.; Egan, R. S.; Perun, T. J . Experientia
1971, 27, 362.
(2) For recent reviews, see: (a) Chu, D. T. W. Med. Res. Rev. 1999,
19, 497-520. (b) Bryskier, A. Expert Opin. Invest. Drugs 1999, 8, 1171-
1194. (c) Bryskier, A. Expert Opin. Invest. Drugs 1997, 6, 1697-1709.
(d) Chu, D. T. W. Expert Opin. Invest. Drugs 1995, 4, 65-94. (e) Wu,
Y. J . Curr. Pharm. Design. 2000, 6, 181-223. (f) Wu, Y. J .; Su, W. G.
Curr. Med. Chem. 2001, 8, 1727-1758.
10.1021/jo020458e CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/28/2002
9146
J . Org. Chem. 2002, 67, 9146-9152

Novel Antibacterial Macrolides
SCHEME 1
SCHEME 2
expanding reaction via intramoleular transesterification
of the 13-membered diolide 4 (Scheme 1). The 13-
membered diolide 4 was expected to be obtained via
oxidative cleavage at the double bond of the enol ether
3, which was readily available from Ery-A. From inspec-
tion of the space-filling model of 4, we perceived that the
two carbonyl groups in the backbone and in the pendant
chain were relatively proximate, and functionalization
of the pendant carbonyl and the subsequent reconstruc-
tion of the larger ring system would be a promising route.
Thus we decided to employ the diolide 4 as a retethered
ring system for effective reannealing of the full macrolide.
Reduction of the pendant carbonyl to the hydroxy group
would realize a synthetic route to the 15-membered
diolide 5. Protection of the sugar moieties was carried
out using Cbz groups.
Con str u ction of a 15-Mem ber ed Sk eleton . Scheme
2 summarizes the synthetic route to the 15-membered
diolides. The starting enol ether 6, which is readily
available from 1 according to literature,6 was protected
with Cbz groups at the 3′-amino group and the 2′-hydroxy
group of the desosaminyl moiety, accompanied by dem-
ethylation at the 3′-amino group.7 Since protection of the
4′′-hydroxy group of the cladinosyl moiety using Cbz-Cl
and DMAP did not give a satisfactory result, an alterna-
tive method was required. Functionalization of the 4′′-
position as the imidazole carbamate 8, followed by
treatment with BnOH/NaH was found effective for af-
fording the 2′,3′,4′′-tris(Cbz) derivative 9 in high yield.8
With the fully protected enol ether derivative 9 in
hand, oxidative cleavage of the double bond was inves-
tigated. Pyridinium chlorochromate (PCC) on Celite
introduced by Chandrasekaran et al.9 for the selective
cleavage of enol ether double bonds furnished the desired
13-membered diolide 10 having an acetonyl side chain
in acceptable yield.
The keto group in the acetonyl side chain was quan-
titatively reduced with an excess (10 equiv) of BH3-THF
complex to yield the corresponding alcohols 11a and 11b
as a 2:1 mixture of stereoisomers. Each isomer was
separable by silica gel column chromatography (11a ,
64%; 11b, 29%). The NaBH4 (10 equiv) reduction was
very sluggish and was not examined in detail. On the
other hand, conversion of the alcohol 11b to 11a was
investigated. The mesylation of 11b, followed by treat-
ment with aqueous THF, gave 11a in good yield. This
displacement is likely to have proceeded via the SN2
mechanism, because 11a was transformed to 11b and
12b by the same procedure.
(6) Murphy, H. W.; Stephens, V. C.; Conine, J . W. USA Patent
3417077 (1968). (b) Slawinski, W.; Bojarska-Dahlig, H.; Glabski, T.;
Dziegielewska, I.; Biedrzycki, M.; Naperty, S. Rec. J . R. Nether. Chem.
Soc. 1975, 94, 236. (c) Hauske. J . R.; Kostek. G. J . Org. Chem. 1982,
47, 1595.
(7) Flynn, E. H.; Murphy, H. W.; McMahon, R. E. J . Am. Chem. Soc.
1955, 77, 3104-3105.
(8) Yasukata, T.; Narukawa, Y. Unpublished results from these
laboratories. This method for Cbz-protection of the cladinosyl moiety
of erythromycin derivatives was originally invented.
(9) Baskaran, S.; Islam, I.; Raghavan, S.; Chandrasekaran, S. Chem.
Lett. 1987, 1175. (b) Kraft, P.; Tochtermann, W. Liebigs Ann. Chem.
1995, 8, 1409.
J . Org. Chem, Vol. 67, No. 26, 2002 9147

Ohara et al.
SCHEME 3
The next stage, the key transesterification, went as
expected. Treatment of 11a and 11b with NaH success-
fully afforded the 15-membered diolides 12a and 12b,
respectively, in excellent yield. Each 15-membered diolide
was deprotected and N-methylated to give 13a and 13b
in high yield.
Deter m in a tion of th e Absolu te Con figu r a tion a t
C-8. Next, we tried to determine the absolute configu-
ration at the C-8 position of the new diolides 13a and
13b. To this end, we transformed 11a and 11b to the
lactam derivatives corresponding to 13a and 13b. The
Merck group reported that 8a-azahomoerythromycin was
obtained via Beckmann rearrangement of erythromycin-
9(Z)-oxime.10 Since the (R)-stereochemistry at the C-8
position was retained under the Beckmann rearrange-
ment conditions, the transformation to the lactam de-
rivatives and comparison with the stereochemically
authentic sample obtained from Merck’s 8-(R)-8a-azaho-
moerythromycin should enable us to determine the
absolute configuration. Also, this transformation would
demonstrate the extension of our synthetic method to the
preparation of lactam analogues. Thus, alcohol 11a and
11b were converted to the 8a-azahomoerythromycin
derivatives in three steps (Scheme 3). 11a and 11b were
converted to the azides 14a and 14b via Mitsunobu
reaction with inversion of the stereochemistry. Staudinger
reduction of 14a and 14b spontaneously gave rise to ring
expansion via lactam formation to produce the desired
15a and 15b, which were deprotected and N-methylated
to give 16a and 16b, respectively.
1
The H NMR of the 11,12-carbonate derived from the
authentic 8-(R)-8a-azahomoerythromycin was consistent
with that of 16b, and not of 16a . Since 11a and 16b have
the same (R)-stereochemistry, taking account of the
inversion at the Mitsunobu reaction, we concluded that
the absolute configuration at the C-8 position of 13a is
R, which is the same as that of Ery-A. Consequently, 13b
has the (S)-configuration. Furthermore, X-ray structure
determination of 13a and 13b was successfully per-
formed, which confirmed their stereochemistry.11 The
superimposition of 13a and 13b with Ery-A (1) is shown
in Figure 1. The stereochemistry and backbone confor-
mation of 13a were similar to those of Ery-A (1) (Figure
1a). Contrarily, the superimposition of 13b indicated very
poor fit. The backbone conformation of 13b deviated from
that of Ery-A(1), so the 6-hydroxy and 9-carbonyl groups
were directed toward the outside of the macrolide nucleus
(Figure 1b).
Syn th esis of 11,12-Diol 18. To investigate the con-
formational effect of the 11,12-cyclic carbonate moiety on
the antibacterial activities, we synthesized 11,12-diol 18.
To this end, we planned to convert the 11,12-cyclic
carbonate 12a into 11,12-diol 17 (Scheme 4). Initial
attempts for removing the cyclic carbonate group under
hydrolytic conditions (K2CO3/MeOH-H2O, or NaOH/
THF-H2O) were unsuccessful and resulted in competi-
tive decomposition of the diolide frame as well as
hydrolysis of Cbz groups in the sugar moieties.12 To
suppress the detrimental side reaction, we turned our
efforts to the use of carbon nucleophiles. In our indepen-
dent studies, we found that treatment of the 13-
membered diolide 10 with MeMgBr in THF (0 °C, 1 h)
afforded the 11-OAc, 12-OH derivative 19, which was
deprotected and N-methylated to give 20 (Scheme 5).
Thus, we expected that the use of a Grignard reagent
would be effective for removing the 11,12-cyclic carbonate
group. However, treatment of 12a with MeMgBr gave
complex mixtures of products without 17 (Table 1, entry
1). Then, we assumed that the use of a bifunctional
Grignard reagent with two nucleophilic sites would be
more effective, since the second nucleophilic attack
should occur intramolecularly. As expected, treatment of
12a with Normant reagent13 successfully gave 17 in 34%
yield (Table 1, entry 2). Furthermore, a bis-Grignard
reagent,14 which was prepared from dibromobutane, was
much more effective, to give 17 in 65% yield (Table 1,
(12) For basic hydrolysis of 11,12-cyclic carbonate of erythromycin
analogues, see: (a) Faghih, R.; Burnell-Curty, C.; Lartey, P. A.;
Peterson, A.; Klein, L. L.; Bennani, Y. L.; Nellans, H. N. Eur. J . Med.
Chem. 1999, 34 (3), 261. (b) Hunt, E.; Tyler, J . W. J . Chem. Soc., Perkin.
Trans. 2. 1990, 2157.
(13) Cahiez, G.; Alexakis, A.; Normant, J . F. Tetrahedron Lett. 1978,
3013.
(14) Cannon, K. C.; Know, G. R. In Handbook of Grignard Reagents;
Silverman, G. S.; Rakita. P. E., Ed.; Marcel Dekker: New York, 1996;
pp 497-526.
(10) Wilkening, R. R.; Ratcliffe, R. W.; Doss, G. A.; Bartizal, K. F.;
Graham, A. C.; Herbert, C. M. Bioorg. Med. Chem. Lett. 1993, 3, 1287.
(b) Wilkening, R. R.; Ratcliffe, R. W.; Doss, G. A.; Mosley, R. T.; Ball,
R. G. Tetrahedron, 1997, 53, 16923.
(11) X-ray crystal structures and crystal data for 13a and 13b are
reported in the Supporting Information.
9148 J . Org. Chem., Vol. 67, No. 26, 2002

Novel Antibacterial Macrolides
TABLE 1. Rem ova l of 11,12-Cyclic Ca r bon a te
entrya
nucleophile (equiv)
MeMgBr (15)
temp (°C)
time
yield (%) of 17
1
2
-78 f 0
-78 f 0
5 h
6 h
complex mixture
34
(15)
(5)
3
-78
2 h, 50 min
65
a
All reactions were performed in THF.
SCHEME 5
TABLE 2. In Vitr o An tiba cter ia l Activity15 (MIC, µg/m L)
of Va r iou s P r od u cts
straina
Ery-A (1) 13a
13b
16a
16b
18
S.a. J C-1
S.p. SR16675
H.i. 88652
0.2
1.56
3.13
3.13 >100 >100 3.13 0.78
1.56 >100
6.25 100
25 6.25 3.13
50 3.13 3.13
a
S.a. ) Staphylococcus aureus; S.p. ) Streptococcus pneumo-
niae; H.i. ) Haemophilus influenzae.
sponding lactam analogues against a panel of both Gram-
positive and Gram-negative organisms are presented
with that of Ery-A (1) as a reference compound in Table
2. The compounds having a natural 8-(R) configuration
(13a , 16b, and 18) had antibacterial activities compa-
rable to that of Ery-A (1), and contrarily, 13b and 16a ,
which had the unnatural 8-(S) configuration, had almost
no antibacterial activities. The 11,12-diol 18 showed the
most potent antibacterial activities among these 15-
membered macrolides.
F IGURE 1. Superimposition of crystal structures: (a) 13a
(green) and Ery-A (1, yellow) and (b) 13b (blue) and Ery-A
(1, yellow).
SCHEME 4
Con clu sion
In conclusion, we established a novel synthetic route
to the 15-membered diolides 13a and 13b and deter-
mined their stereochemistry. The antibacterial activities
of the diolides, 13a , 13b, and 18 and their corresponding
lactams 16a and 16b were evaluated, which revealed that
the natural 8-(R)-13a , 8-(R)-16b, and 8-(R)-18 have much
more potent activities than the unnatural 8-(S)-13b and
8-(S)-16a . The structure-activity relationship of their
related compounds will be reported elsewhere.
Exp er im en ta l Section
8,9-An h yd r o-2′-O,3′-N-bis(ben zyloxyca r bon yl)-3′-N-d e-
m eth yler yth r om ycin A 6,9-Hem ik eta l Cyclic 11,12-Ca r -
entry 2). It is noteworthy that chemoselective removal
of 11,12-cyclic carbonate was performed with the Cbz
groups intact. Finally, 17 was deprotected and N-methy-
lated to give 18 in 97% yield (Scheme 4).
(15) MICs (minimum inhibitory concentrations) were determined
by NCCLS (National Committee for Clinical Laboratory Standards)
recommended microbroth dilution methods using cation-adjusted
Mueller Hinton broth (Difco Laboratories, Detroit, MI).
An tiba cter ia l Activity. The in vitro antibacterial
activities15 of the 15-membered diolides and the corre-
J . Org. Chem, Vol. 67, No. 26, 2002 9149

Ohara et al.
bon a te (7). A slurry of 66 (40.0 g, 54.0 mmol) and NaHCO3
(68.0 g, 0.81 mol) in 1,4-dioxane (70 mL) was heated to 71 °C.
Cbz-Cl (92.1 g, 0.54 mol) was dropwise added to the mixture,
the temperature of which was maintained at 70-75 °C during
the addition. After being stirred at the same temperature for
1 h, the reaction mixture was cooled to room temperature and
then treated with Et3N (1.5 mL, 10.8 mmol) and stirred for
another hour. The insoluble salt was filtered off and washed
with a 1:1 mixture of CHCl3 and n-hexane (400 mL). The
filtrate was concentrated and the remaining benzyl alcohol was
removed by distillation at 70 °C under reduced pressure. The
resultant residue was purified by column chromatography on
silica gel (n-hexane:EtOAc ) 2:1) to give 54.3 g (quant) of 7
as a colorless foam: IR (CHCl3) νmax 3550, 2968, 2930, 1796,
1742, 1692, 1453, 1381, 1329 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.38, 3.02 (two s, 3H), 2.85, 2.81 (two s, 3H); 13C NMR (75
MHz, CDCl3) δ 176.6, 156.6, 156.2, 154.7, 154.6, 153.2, 147.7,
136.7, 136.6, 135.5, 135.3, 128.5, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 127.7, 104.9, 100.5, 95.1, 95.0, 87.4, 87.2, 85.1,
82.5, 79.9, 79.7, 78.1, 76.1, 76.0, 75.7, 74.9, 74.8, 73.0, 69.7,
69.5, 68.3, 67.5, 67.19, 65.6 (2C), 54.8, 49.7, 49.1, 43.7, 43.1,
41.7, 36.4, 35.9, 34.6, 31.9, 28.7, 25.4, 22.3, 21.6, 20.8, 18.3,
15.7, 13.5, 12.8, 12.2, 10.6, 8.2; MS (FAB) m/z 995 (M+), 412,
260, 170, 91; HRFABMS calcd for C53H73NNaO17 (M+ + Na)
m/z 1018.4777, found m/z 1018.4766.
34.7, 34.6, 31.7, 31.6, 24.9, 22.4, 21.1, 21.0, 17.9, 17.8, 15.8,
12.9, 11.7, 10.6, 8.2; MS (FAB) m/z 1184 (M+ + Na), 170, 91;
HRFABMS calcd for C61H79NNaO21 (M+ + Na) m/z 1184.5042,
found m/z 1184.5040.
3′-N -De m e t h yl-6-d e oxy-6,9-e p oxy-6-[(R )-2-h yd r oxy-
p r op yl]-7,8-n or -2′-O,3′-N,4′′-O-t r is(b en zyloxyca r b on yl)-
er yth r om ycin A Cyclic 11,12-Ca r bon a te (11a ) a n d 3′-N-
Dem eth yl-6-d eoxy-6,9-ep oxy-6-[(S)-2-h yd r oxyp r op yl]-7,8-
n o r -2′-O ,3′-N ,4′′-O -t r is (b e n zy lo x y c a r b o n y l)e r y t h r o -
m ycin A Cyclic 11,12-Ca r bon a te (11b). To a solution of 10
(19.0 g, 16.4 mmol) in THF (190 mL) was dropwise added
BH3-THF complex (1.0 M solution in THF, 164 mL) at ice-
bath temperature over 35 min. The mixture was stirred at the
same temperature for 1.5 h and diluted with EtOAc (500 mL).
Under cooling with an ice-bath, 5% aqueous NaHCO3 was
added dropwise and the mixture was stirred at the ice-bath
temperature for 1 h. After usual workup, the resultant residue
was purified by column chromatography on silica gel (n-
hexane:EtOAc ) 3:2) to afford 12.2 g (64%) of the more polar
(R)-isomer 11a and 5.45 g (29%) of the less polar (S)-isomer
11b, respectively, as white crystals.
Compound 11a : mp 201-203 °C (n-hexane, EtOAc); IR
(CHCl3) νmax 3500, 2972, 2936, 1805, 1740, 1693, 1453, 1383,
1332 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.38, 2.87 (two s, 3H),
2.83, 2.78 (two s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.0,
171.9, 156.7, 156.3, 155.5, 154.9, 154.8, 152.5, 136.7, 136.5,
135.2, 135.1, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9,
127.6, 98.9, 95.3, 95.2, 89.9, 85.2, 82.3, 81.6, 80.7, 75.2, 75.0,
74.7, 74.6, 72.7, 72.6, 69.9, 69.8, 69.7, 67.6, 67.2, 64.3, 63.1,
54.3, 49.3, 48.7, 44.1, 43.3, 43.2, 42.9, 42.8, 36.3, 35.8, 34.7, 34.5,
28.5, 24.8, 22.9, 22.3, 21.1, 21.0, 17.8, 16.0, 13.3, 11.7, 10.5,
8.6; MS (FAB) m/z 1186 (M+ + Na), 91; HRFABMS calcd for
8,9-An h yd r o-3′-N-d em et h yl-2′-O,3′-N,4′′-O-t r is(b en z-
yloxyca r bon yl)er yth r om ycin A 6,9-Hem ik eta l Cyclic 11,-
12-Ca r bon a te (9). To a solution of 7 (54.3 g, 54.5 mmol) in
THF (540 mL) were added K2CO3 (14.9 g, 0.108 mol) and 1,1′-
carbonyldiimidazole (13.1 g, 81.0 mmol), and the mixture was
stirred at room temperature for 1 h. Next, K2CO3 (8.96 g, 64.8
mmol) and 1,1′-carbonyldiimidazole (8.76 g, 54.0 mmol) were
added to the mixture, which was stirred for another hour. After
filtration, the filtrate was evaporated and worked up in EtOAc
to give 60.6 g of crude 8. To a solution of the crude 8 in THF
(500 mL) were added benzyl alcohol (11.2 mL, 0.108 mol) and
NaH (60% in oil, 2.81 g, 70.3 mmol) at room temperature. The
reaction mixture was stirred for 1 h at the same temperature
and quenched with ice-cold 10% aqueous H3PO4 (500 mL). The
resultant mixture was worked up in EtOAc and the crude
product was purified by column chromatography on silica gel
(n-hexane:EtOAc ) 5:1 and 3:1) to give 48.7 g (80%) of 9 as a
colorless foam. IR (CHCl3) νmax 2970, 2932, 1796, 1740, 1692,
1452, 1382, 1334 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.36, 2.94
(two s, 3H), 2.83, 2.79 (two s, 3H); 13C NMR (75 MHz, CDCl3)
δ 176.6, 156.6, 156.2, 155.6, 154.7, 154.6, 153.2, 147.6, 136.7,
136.5, 135.5, 135.2, 128-127, 104.8 (2C), 100.0, 95.1, 95.0, 87.1,
85.1, 82.7, 82.5, 79.6, 76.2, 76.1, 75.7, 75.1, 75.0, 72.7, 69.8,
69.7, 69.6, 69.4, 67.6, 67.5, 67.1, 63.0, 54.8, 49.5, 49.0, 43.4,
42.9, 41.5, 36.4, 35.9, 34.8, 31.9, 28.7, 25.5, 22.3, 20.9, 17.8,
15.7, 13.4, 12.7, 12.2, 10.6, 8.1; MS (FAB) m/z 1129(M+), 412,
293, 261, 260, 170, 91; HRFABMS calcd for C61H79NNaO19
(M+ + Na) m/z 1152.5144, found m/z 1152.5148.
3′-N -De m e t h yl-6-d e oxy-6,9-e p oxy-7,8-n or -6-(2-oxo-
p r op yl)-2′-O,3′-N,4′′-O-t r is(b en zyloxyca r b on yl)er yt h r o-
m ycin A Cyclic 11,12-Ca r bon a te (10). To a suspension of
PCC (98%, 47.8 g, 0.217 mol) and Celite (57 g) in 1,2-
dichloroethane (350 mL) was dropwise added a solution of 9
(24.4 g, 21.6 mmol) in 1,2-dichloroethane (200 mL) at room
temperature and the mixture was stirred at 50-55 °C for 8 h.
The mixture was filtered through a pad of Celite and purified
by column chromatography on silica gel (n-hexane:EtOAc )
2:1). The combined pure fractions were crystallized from
methanol to give 10.6 g (42%) of 10 as white crystals: mp 170-
171 °C (MeOH); IR (CHCl3) νmax 2972, 2936, 1804, 1737, 1695,
1453, 1383, 1332 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.37, 2.96
(two s, 3H), 2.84, 2.79 (two s, 3H); 13C NMR (75 MHz, CDCl3)
δ 205.0, 176.4, 171.7, 156.7, 156.2, 155.5, 154.7, 154.6, 152.6,
136.8, 136.4, 135.3, 135.3, 135.2, 128.6, 128.5, 128.4, 128.2,
128.1, 128.0, 127.9, 127.6, 98.9, 95.2, 95.1, 86.7, 86.6, 85.6, 82.4,
81.6, 80.0, 75.0, 74.8, 72.7, 72.6, 69.9, 69.8, 69.6, 67.6, 67.1,
63.0, 54.6, 49.3, 48.7, 46.8, 46.7, 43.8, 42.8, 42.1, 36.3, 35.8,
C
61H81NNaO21 (M+ + Na) m/z 1186.5199, found m/z 1186.5206.
Compound 11b: mp 133-134 °C (n-hexane, EtOAc); IR
(CHCl3) νmax 3528, 2972, 2934, 1805, 1740, 1693, 1453, 1383,
1333 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.39, 2.86 (two s, 3H),
2.81, 2.76 (two s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.0,
171.4, 156.7, 156.2, 155.5, 154.9, 152.5, 136.7, 136.4, 135.2,
135.1, 135.0, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0,
127.9, 127.6, 99.4, 95.6, 95.5, 89.9, 85.2, 82.3, 81.7, 80.9, 75.0,
74.9, 74.1, 72.7, 72.6, 70.2, 69.9, 70.2, 70.0, 69.9, 67.7, 67.6,
67.2, 63.8, 63.2, 54.4, 49.3, 48.7, 44.5, 42.7, 42.6, 36.2, 35.7,
34.6, 34.5, 28.5, 25.1, 22.3, 22.1, 21.1, 20.9, 17.9, 17.8, 16.3,
13.0, 11.7, 10.5, 8.1; MS (FAB) m/z 1186 (M+ + Na), 91;
HRFABMS calcd for C61H81NNaO21 (M+ + Na) m/z 1186.5199,
found m/z 1186.5197.
Con ver sion of Alcoh ol 11b to 11a by In ver sion of C-8
Ster eoch em istr y. To a cooled solution of 11b (2.00 g, 1.72
mmol) in CH2Cl2 (20 mL) were added Et3N (2.4 mL, 17.2 mmol)
and MsCl (1.3 mL, 17.2 mmol) at -40 to -30 °C. The reaction
mixture was stirred at the same temperature for 2 h and
worked up in EtOAc. The resultant mesylated product (2.48
g) was dissolved in a 4:1 mixture (100 mL) of THF and water
and heated at 75 °C for 2.5 h. After the mesylated product
had disappeared from the TLC, the reaction mixture was
concentrated and worked up in EtOAc. The crude product was
purified by column chromatography on silica gel (n-hexane:
EtOAc ) 3:2) to give 1.46 g (73%) of 11a as a colorless foam.
8-(R)-3′-N-Dem eth yl-8a -oxa -2′-O,3′-N,4′′-O-tr is(ben zyl-
oxyca r b on yl)-8a -h om oer yt h r om ycin A Cyclic 11,12-
Ca r bon a te (12a ). To a solution of 11a (12.2 g, 10.5 mmol) in
THF (120 mL) was added portionwise NaH (60% in oil; 629
mg, 15.7 mmol), and the mixture was stirred for 50 min at
room temperature. The reaction was quenched with 10% HCl
(4.8 mL) and diluted with water. The mixture was then worked
up in EtOAc. The crude product was purified by column
chromatography on silica gel (n-hexane:EtOAc ) 3:1 and 2:1)
to give 11.9 g (98%) of 12a as a colorless foam. IR (CHCl3)
ν
max 3520, 2972, 2934, 1802, 1738, 1692, 1454, 1382, 1333 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.38, 2.98 (two s, 3H), 2.83, 2.80
(two s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.2, 176.1, 172.0,
156.6, 156.3, 155.5, 154.8, 154.7, 152.8, 136.8, 136.6, 135.5,
9150 J . Org. Chem., Vol. 67, No. 26, 2002

Novel Antibacterial Macrolides
135.3, 135.2, 98.9, 98.8, 95.1, 85.5, 82.6, 82.3, 82.2, 81.5, 76.2,
76.1, 75.2, 75.0, 74.0, 72.7, 72.6, 69.8, 69.7, 69.6, 69.4, 67.8,
67.5, 67.1, 63.2, 54.7, 49.4, 48.9, 44.5, 41.8, 40.6, 40.5, 36.3,
35.8, 35.0, 34.9, 28.9, 25.5, 22.9, 22.1, 21.2, 21.1, 20.8, 17.7,
15.5, 15.0, 12.8, 10.5, 8.9; MS (FAB) m/z 1186 (M+ + Na), 170,
1.18 (four d and s, 15H), 1.18 (partially hidden-dd, 1H), 0.90
(t, 3H, J ) 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 174.77,
170.33, 153.72, 104.82, 98.99, 84.59, 84.18, 84.04, 83.11, 77.59,
77.38, 75.02, 72.58, 70.39, 69.62, 69.47, 65.91 (two carbon
signals crossed over each other), 49.23, 45.43, 44.77, 41.06,
40.23, 39.84, 35.82, 30.82, 28.19, 22.33, 21.42, 21.37, 21.20,
17.37, 16.30, 13.22, 11.37, 10.01, 8.81; MS (FAB) m/z 776 (M+
+ H), 618, 158; HRFABMS calcd for C38H66NO15 (M+ + H) m/z
776.4433, found m/z 776.4430. Anal. Calcd for C38H65NO15‚0.5-
H2O: C, 58.15;H, 8.48;N, 1.78. Found: C, 58.19;H, 8.44;N, 1.98.
3′-N-Dem eth yl-6-deoxy-6,9-epoxy-6-[(S)-2-azidopr opyl]-
7,8-n or -2′-O,3′-N,4′′-O-t r is(b en zyloxyca r b on yl)er yt h r o-
m ycin A Cyclic 11,12-Ca r bon a te (14a ). To a solution of 11a
(500 mg, 0.43 mmol) in THF (7.5 mL) was added triph-
enylphosphine (564 mg, 2.15 mmol), hydrogen azide (1.7 M
solution in toluene, 2.5 mL, 4.25 mmol), and DEAD (0.34 mL,
2.16 mmol) successively under ice-cooling. The mixture was
stirred for 40 min at ice-bath temperature. The reaction was
quenched with water and the mixture was worked up in
EtOAc. The crude product was purified by column chroma-
tography on silica gel (n-hexane:EtOAc ) 2:1) to give 445 mg
(87%) of 14a as a colorless foam: IR (CHCl3) νmax 2972, 2936,
2100, 1805, 1740, 1692, 1453, 1383, 1333 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.39, 2.86 (two s, 3H), 2.83, 2.79 (two s, 3H);
13C NMR (75 MHz, CDCl3) δ 176.2, 171.5, 156.7, 156.3, 155.5,
154.7, 154.6, 152.6, 136.8, 136.5, 135.4, 135.3, 135.2, 128.7,
128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6,
98.9, 98.6, 95.2, 95.1, 88.5, 85.3, 82.4, 81.6, 80.6, 75.1, 75.0,
72.7, 72.6, 69.9, 69.8, 69.5, 67.6, 67.1, 63.1, 54.6, 54.1, 49.3,
48.7, 43.8, 42.9, 42.7, 40.0, 36.3, 35.8, 34.7, 34.5, 28.6, 23.0,
22.4, 21.1, 21.0, 20.8, 17.8, 15.6, 13.2, 11.8, 10.5; MS (FAB)
m/z 1211 (M+ + Na), 412, 261, 170, 91; HRFABMS calcd for
C61H80N4NaO20 (M+ + Na) m/z 1211.5263, found m/z 1211.5255.
3′-N-Dem eth yl-6-deoxy-6,9-epoxy-6-[(R)-2-azidopr opyl]-
7,8-n or -2′-O,3′-N,4′′-O-t r is(b en zyloxyca r b on yl)er yt h r o-
m ycin A Cyclic 11,12-Ca r bon a te (14b). Compound 14b was
prepared from 11b in 42% yield as a colorless foam by the same
procedure as 14a . IR (CHCl3) νmax 2972, 2936, 2102, 1804,
1741, 1692, 1452, 1384, 1333 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.38, 2.88 (two s, 3H), 2.82, 2.78 (two s, 3H); 13C NMR (75
MHz, CDCl3) δ 175.7, 171.2, 156.4, 155.9, 155.2, 154.5, 154.4,
152.3, 150.4, 136.5, 136.3, 135.1, 135.0, 134.9, 128.4, 128.3,
128.1, 127.9, 127.8, 127.7, 127.6, 98.5, 95.0, 94.9, 88.1, 88.0,
85.1, 82.2, 81.5, 80.4, 75.2, 75.0, 74.9, 72.6, 72.5, 70.8, 69.8,
69.7, 69.4, 67.4, 67.3, 67.0, 64.2, 63.0, 54.3, 54.1, 49.2, 48.5,
43.5, 43.4, 42.8, 42.6, 39.0, 36.2, 35.7, 34.6, 34.5, 32.2, 32.0,
28.4, 26.2, 22.4, 22.0, 21.9, 21.6, 21.1, 21.0, 20.9, 17.7, 17.6,
15.7, 15.6, 14.1, 13.4, 11.6, 10.4, 8.4; MS (FAB) m/z 1211 (M+
+ Na), 412, 293, 261, 260, 170, 91; HRFABMS calcd for
C61H80N4NaO20 (M+ + Na) m/z 1211.5263, found m/z 1211.5261.
91; HRFABMS calcd for
C
61H81NNaO21 (M+ + Na) m/z
1186.5199, found m/z 1186.5195.
8-(R)-8a -Oxa -8a -h om oer yth r om ycin A Cyclic 11,12-
Ca r bon a te (13a ). A solution of 12a (2.00 g, 1.72 mmol) in
0.5 M acetate buffer (pH 4.5, 36 mL) and EtOH (180 mL) was
stirred at room temperature for 1.5 h under H2 atmosphere
in the presence of 20% Pd(OH)2/C (400 mg). Next, 37% HCHO
(13 mL) was added to the reaction mixture and the stirring
was continued for another hour under the same conditions.
The mixture was filtered and concentrated. After being diluted
with water, the mixture was basified with 5% aqueous
NaHCO3 and then worked up in EtOAc. The resultant residue
was crystallized from acetone and water to yield 1.25 g (94%)
of 13a as white crystals: mp 207-208 °C (H2O, acetone); IR
(CHCl3) νmax 3430, 2970, 2932, 1801, 1732, 1456, 1378, 1318
1
cm-1; H NMR (600 MHz, CDCl3) δ 5.29 (sextet, 1H, J ) 5.8
Hz), 5.02 (dd, 1H, J ) 9.3 Hz, 3.3 Hz), 4.89 (d, 1H, J ) 4.2
Hz), 4.82 (d, 1H, J ) 7.2 Hz), 4.48 (d, 1H, J ) 7.8 Hz), 4.31 (t,
1H, J ) 4.2 Hz), 4.04 (dq, 1H, J ) 9.0 Hz, 6.0 Hz), 3.68 (d, 1H,
J ) 6.0 Hz), 3.56 (ddq, 1H, J ) 10.8 Hz, 1.4 Hz, 6.0 Hz), 3.31
(s, 3H), 3.26 (dd, 1H, J ) 10.5 Hz, 7.5 Hz), 3.04 (d, 1H, J )
9.0 Hz), 2.71 (quintet, 1H, J ) 6.6 Hz), 2.67 (qd, 1H, J ) 6.9
Hz, 4.5 Hz), 2.50 (ddd, 1H, J ) 12.0 Hz, 10.2 Hz, 3.6 Hz), 2.35
(d, 1H, J ) 15.0 Hz), 2.29 (s, 6H), 1.88 (m, 1H), 1.81 (m, 1H),
1.77 (dd, 1H, J ) 14.7 Hz, 5.7 Hz), 1.72-1.66 (m, 3H), 1.65
(m, 1H), 1.59 (dd, 1H, J ) 15.0 Hz, 4.8 Hz), 1.42 (s, 3H), 1.36
(d, 3H, J ) 6.6 Hz), 1.32 (d, 3H, J ) 7.2 Hz), 1.30 (s, 3H), 1.29
(d, 3H, J ) 6.6 Hz), 1.25-1.23 (two d and s, 9H), 1.10 (d, 3H,
J ) 7.2 Hz), 0.93 (t, 3H, J ) 7.5 Hz); 13C NMR (150 MHz,
CDCl3) δ 175.6, 171.9, 152.9, 103.7, 96.3, 85.8, 84.1, 81.9, 78.2,
77.7, 77.0, 73.9, 72.8, 70.6, 69.8, 69.5, 65.9, 65.2, 49.4, 45.3,
42.4, 41.7, 40.4, 40.3, 35.0, 28.7, 26.1, 22.8, 22.0, 21.5, 21.2,
18.0, 15.9, 14.3, 13.0, 10.5, 10.0; MS (FAB) m/z 776 (M+ + H),
618, 158; HRFABMS calcd for C38H66NO15 (M+ + H) m/z
776.4433, found m/z 776.4434. Anal. Calcd for C38H65NO15‚1.3-
H2O: C, 57.10;H, 8.52;N, 1.75. Found: C, 57.11;H, 8.42;N, 1.84.
8-epi-(S)-3′-N-Dem eth yl-8a -oxa -2′-O,3′-N,4′′-O-tr is(ben z-
yloxyca r bon yl)-8a -h om oer yth r om ycin A Cyclic 11,12-
Ca r bon a te (12b). Compound 12b was prepared from 11b in
90% yield as a colorless foam by the same procedure as 12a .
IR (CHCl3) νmax 3500, 2974, 2934, 1802, 1736, 1693, 1454, 1382,
1332 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.34, 3.02 (two s, 3H),
2.81, 2.78 (two s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.0,
170.2, 156.6, 156.1, 155.4, 154.4, 154.3, 152.9, 136.7, 136.6,
135.2, 135.1, 128.6, 128.5, 128.1, 128.0, 127.9, 127.8, 127.6,
99.8, 96.4, 85.5, 84.2, 83.9, 82.3, 82.1, 78.1, 75.0, 74.0, 72.5,
70.5, 69.9, 69.8, 69.6, 68.4, 67.4, 67.1, 63.4, 54.9, 49.4, 49.0,
45.2, 45.0, 44.8, 42.0, 40.8, 36.3, 35.8, 35.2, 35.1, 29.0, 22.5,
21.2, 20.9, 20.8, 17.5, 17.4, 15.5, 14.2, 14.1, 14.0, 12.5, 12.4,
10.6, 9.2, 9.1; MS (FAB) m/z 1186 (M+ + Na), 412, 293, 261,
260, 170, 91; HRFABMS calcd for C61H81NNaO21 (M+ + Na)
m/z 1186.5199, found m/z 1186.5227.
8-epi-(S)-8a -Oxa -8a -h om oer yt h r om ycin A Cyclic 11,-
12-Ca r bon a te (13b). Compound 13b was prepared from 12b
in 89% yield as white crystals by the same procedure as 13a :
mp 149-151 °C (H2O, acetone); IR (CHCl3) νmax 3540, 3434,
2968, 2930, 1798, 1731, 1455, 1374, 1360 cm-1; 1H NMR (600
MHz, CDCl3) δ 5.52 (s, 1H), 5.07 (dd, 1H, J ) 10.8 Hz, 1.8
Hz), 5.00 (qd, 1H, J ) 6.0 Hz, 8.4 Hz), 4.83 (d, 1H, J ) 3.6
Hz), 4.71 (d, 1H, J ) 9.0 Hz), 4.25 (d, 1H, J ) 7.2 Hz), 4.08
(dq, 1H, J ) 9.6 Hz, 6.0 Hz), 3.89 (s, 1H), 3.45 (m, 1H), 3.32
(bs,1H), 3.28 (d, 1H, J ) 9.6 Hz), 3.25 (s, 3H), 3.10-3.00 (m,
3H), 2.79 (dq, 1H, J ) 9.6 Hz, J ) 6.6 Hz), 2.41 (ddd, 1H),
2.34 (d, 1H, J ) 9.6 Hz), 2.32 (bs, 1H), 2.25 (s, 6H), 2.20 (dd,
1H, J ) 15.0 Hz, 8.4 Hz), 2.10 (m, 1H), 1.88 (m, 1H), 1.65-
1.55 (m, 3H), 1.47 (d, 1H, J ) 15.0 Hz), 1.47 (s, 3H), 1.40 (s,
3H), 1.34 (d, 3H, J ) 6.6 Hz), 1.27 (d, 3H, J ) 6.6 Hz), 1.28-
8-epi-(S)-8a -Aza -3′-N-d em eth yl-2′-O,3′-N,4′′-O-tr is(ben z-
yloxyca r bon yl)-8a -h om oer yth r om ycin A Cyclic 11,12-
Ca r bon a te (15a ). To a solution of 14a (250 mg, 0.21 mmol)
in THF (7.5 mL) was added triphenylphosphine (442 mg, 1.69
mmol), and the mixture was stirred for 1 h at room temper-
ature. Next, water (0.24 mL) was added to the mixture, which
was heated at 60 °C for 3 h. After being cooled, the reaction
mixture was diluted with water and worked up in EtOAc. The
crude product was purified by column chromatography on
silica gel (n-hexane:EtOAc ) 1:1) to give 128 mg (52%) of 15a
as a colorless foam: IR (CHCl3) νmax 3500, 2972, 2934, 1799,
1737, 1691, 1508, 1453, 1382, 1334 cm-1; 1H NMR (300 MHz,
CDCl3) δ 3.36, 2.98 (two s, 3H), 2.83, 2.79 (two s, 3H); 13C NMR
(75 MHz, CDCl3) δ 177.2, 170.9, 156.6, 156.2, 155.5, 154.7,
154.6, 152.9, 136.8, 136.6, 135.4, 135.3, 135.2, 128.7, 128.6,
128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127,8, 127.6, 99.2, 95.1,
95.0, 86.8, 83.9, 82.6, 82.2, 75.1, 75.0, 74.8, 72.6, 69.9, 69.8,
69.6, 68.0, 67.5, 67.1, 63.2, 54.6, 49.4, 49.0, 44.7, 44.2, 43.4,
42.5, 42.4, 41.1, 36.3, 35.8, 35.0, 34.9, 28.8, 22.4, 21.1, 21.0,
20.9, 17.6, 15.4, 14.9, 13.5, 10.5, 8.9; MS (FAB) m/z 1163 (M+
+ H), 412, 170, 91; HRFABMS calcd for C61H82N2O20 (M+
H) m/z 1185.5359, found m/z 1185.5360.
+
J . Org. Chem, Vol. 67, No. 26, 2002 9151

Ohara et al.
8-(R)-8a -Aza -3′-N-d em eth yl-2′-O,3′-N,4′′-O-tr is(ben zyl-
oxyca r b on yl)-8a -h om oer yt h r om ycin A Cyclic 11,12-
Ca r bon a te (15b). Compound 15b was prepared from 14b in
88% yield as a colorless foam by the same procedure as 15a .
IR (CHCl3) νmax 3420, 2970, 2934, 1797, 1740, 1691, 1510, 1453,
1382, 1333 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.40, 2.98 (two
s, 3H), 2.83, 2.80 (two s, 3H); 13C NMR (75 MHz, CDCl3) δ
176.0, 171.0, 156.6, 156.3, 155.5, 154.8, 154.7, 152.9, 136.8,
136.6, 135.5, 135.4, 135.3, 128.7, 128.6, 128.5, 128.4, 128.1,
127.9, 127.8, 127.7, 127.6, 98.5, 95.0, 94.9, 86.0, 85.3, 84.7, 82.7,
81.7, 75.4, 75.1, 74.1, 72.7, 69.8, 69.7, 69.6, 69.5, 69.4, 67.5,
67.4, 67.1, 63.1, 54.7, 49.3, 48.8, 44.4, 44.1, 42.9, 42.3, 42.1,
36.3, 35.8, 35.0, 28.9, 25.0, 22.8, 22.6, 21.3, 20.8, 17.7, 17.6,
16.2, 16.1, 14.5, 10.1, 8.9, 8.8; MS (FAB) m/z 1185 (M+ + Na),
170, 91; HRFABMS calcd for C61H82N2O20 (M+ + H) m/z
1185.5359, found m/z 1185.5359.
67.2, 67.1, 65.2, 62.9, 54.6, 49.5, 44.9, 41.7, 41.2, 39.3, 36.5,
36.0, 34.9, 27.5, 22.4, 21.9, 21.0, 17.9, 17.8, 16.6, 14.9, 11.3,
9.6, 8.6, 8.5; MS (FAB) m/z 1160 (M+ + Na); HRFABMS calcd
for
C
60H83NNaO20 (M+ + Na) m/z 1160.5406, found m/z
1160.5431.
8-(R)-8a -Oxa -8a -h om oer yth r om ycin A (18). Compound
18 was prepared from 17 in 97% yield as a white powder by
the same procedure as 13a : IR νmax (CHCl3) 3532, 3438, 2968,
2932, 1718, 1454, 1378, 1325 cm-1; 1H NMR (300 MHz, CDCl3)
δ 5.27 (m, 1H), 4.91 (d, 1H, J ) 4.5 Hz), 4.80 (dd, 1H, J ) 9.8
Hz, 2.6 Hz), 4.42 (d, 1H, J ) 7.2 Hz), 4.27 (dd, 1H, J ) 6.6 Hz,
3 Hz), 4.02 (m, 1H), 3.85 (bs, 1H), 3.51 (d, 1H, J ) 7.5 Hz),
3.49 (m, 1H), 3.33 (s, 3H), 3.23 (dd, 1H, J ) 9.9 Hz, 7.2 Hz),
3.04 (d, 1H, J ) 9.0 Hz), 2.82-2.66 (m, 2H), 2.49 (m, 1H), 2.35
(d, 1H, J ) 12 Hz), 2.33 (s, 6H), 2.0-1.8 (m, 3H), 1.7-1.5 (m,
5H), 1.42 (s, 3H), 1.30 (d, 3H, J ) 6.3 Hz), 1.24-1.20 (four d
and s, 15H), 1.15 (s, 3H), 1.08 (d, 3H, J ) 7.5 Hz), 0.91 (t, 3H,
J ) 7.4 Hz); 13C NMR (75 MHz, CDCl3) δ 178.6, 174.9, 103.3,
95.2, 83.3, 76.7, 75.7, 74.9, 72.8, 70.9, 70.3, 69.0, 67.3, 65.6,
65.5, 49.5, 45.5, 42.2, 41.2, 40.4, 40.1, 34.7, 28.8, 27.6, 22.4,
21.9, 21.6, 21.4, 18.3, 16.7, 15.0, 11.3, 9.5, 9.3; MS (FAB) m/z
750 (M + H); HRFABMS calcd for C37H68NO14 (M+ + H) m/z
750.4640, found m/z 750.4637.
8-epi-(S)-8a -Aza -8a -h om oer yth r om ycin A Cyclic 11,12-
Ca r bon a te (16a ). Compound 16a was prepared from 15a in
96% yield as white powder by the same procedure as 13a : IR
(CHCl3) νmax 3418, 2970, 2932, 1798, 1731, 1656, 1523, 1456,
1
1376 cm-1; H NMR (300 MHz, CDCl3) δ 6.98 (bs, 1H), 4.96
(dd, 1H, J ) 9.6 Hz, 3.3 Hz), 4.83 (d, 1H, J ) 4.5 Hz), 4.44-
4.30 (m, 3H), 4.06 (dq, 1H, J ) 9.6 Hz, 6.0 Hz), 4.0 (m, 1H),
3.54 (m, 1H), 3.40 (d, 1H, J ) 5.1 Hz), 3.33 (m, 1H), 3.28 (s,
3H), 3.02 (d, 1H, J ) 9.0 Hz), 2.81 (m, 1H), 2.67 (dq, 1H, J )
6.9 Hz, 5.4 Hz), 2.57 (m, 1H), 2.32 (s, 6H), 2.30 (m, 1H), 2.10-
1.45 (m, 11H), 1.61 (s, 3H), 1.40-1.20 (m, 21H), 1.13 (d, 3H, J
) 7.2 Hz), 0.93 (t, 3H, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3)
δ 176.2, 170.3, 152.7, 104.5, 96.5, 86.6, 84.8, 82.9, 77.9, 75.9,
72.7, 70.8, 69.9, 66.0, 64.8, 49.4, 44.6, 44.2, 43.6, 42.0, 41.7,
40.5, 35.0, 29.4, 26.2, 22.5, 22.2, 21.5, 21.2, 18.0, 5.7, 14.6, 13.8,
10.5, 10.5; MS (FAB) m/z 775 (M+ + H), 617, 158; HRFABMS
calcd for C38H67N2O14 (M+ + H) m/z 775.4592, found m/z
775.4589.
3′-N-Dem eth yl-6-d eoxy-6,9-ep oxy-6-(2-h yd r oxy-2-m eth -
ylp r op yl)-7,8-n or -2′ -O,3′-N,4′′-O-tr is(ben zyloxyca r bon yl)-
11-O-a cetyler yth r om ycin A (19). Compound 10 (500 mg,
0.43 mmol) was dissolved in THF (5 mL) and cooled to -78
°C under N2 atmosphere. To this solution was added slowly
MeMgBr (0.92 M in THF), and the mixture stirred at 0 °C for
1 h. After consumption of 10 was confirmed by TLC, 10%
aqueous H3PO4, 10% aqueous HCl and EtOAc were added into
the reaction mixture. The mixture was worked up in EtOAc
to yield a crude product. Purification by silica gel chromatog-
raphy (n-hexane:EtOAc ) 1:1) afforded 260 mg (51%) of 19 as
a colorless foam: IR (CHCl3) νmax 3015, 2978, 1741, 1696, 1456,
1383, 1262 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.28, 2.89 (two
s, 3H), 2.83, 2.80 (two s, 3H); 13C NMR (75 MHz, CDCl3) δ
178.1, 176.1, 175.2, 169.5, 156.6, 156.3, 155.5, 154.8, 136.8,
136.5, 135.4, 135.3, 135.2, 128.5, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 127.8, 98.2, 94.1, 93.9, 89.6, 82.5, 80.4, 80.1, 75.7,
75.0, 72.8, 70.8, 69.7, 67.5, 67.1, 62.9, 54.5, 49.1, 48.5, 44.8,
42.9, 42.7, 42.2, 36.4, 35.8, 32.1, 31.4, 28.7, 24.6, 23.4, 21.4,
21.3, 21.0, 20.7, 15.8, 11.5, 11.2, 9.3; MS (FAB) m/z 1216 (M+
+ Na); HRFABMS calcd for C63H87NNa O21 (M+ + Na) m/z
1216.5668, found m/z 1216.5685.
8-(R)-8a -Aza -8a -h om oer yt h r om ycin A Cyclic 11,12-
Ca r bon a te (16b). Compound 16b was prepared from 15b in
57% yield as white crystals by the same procedure as 13a : IR
(CHCl3) νmax 3420, 2968, 2932, 1796, 1736, 1670, 1509, 1456,
1
1379 cm-1; H NMR (300 MHz, CDCl3) δ 5.58 (d, 1H, J ) 5.6
Hz), 5.22 (dd, 1H, J ) 9.3 Hz, 3.6 Hz), 4.97 (1H, d, J ) 3.9
Hz), 4.66 (d, 1H, J ) 9.0 Hz), 4.53 (d, 1H, J ) 7.2 Hz), 4.39
(dd, 1H, 5.7 Hz, 2.7 Hz), 4.20 (m, 1H), 4.11 (bm, 1H), 4.06 (dq,
1H, J ) 9.0 Hz, 6.0 Hz), 3.81 (bs, 1H), 3.77(d, 1H, J ) 5.4 Hz),
3.59 (m, 1H), 3.31 (s, 3H), 3.30 (d, 1H, J ) 7.2 Hz), 3.06 (t,
3H, J ) 9.6 Hz), 2.71-2.44 (m, 3H), 2.34 (s, 6H), 2.40-2.30 (d
× 2, 2H), 1.90-1.55 (m, 7H), 1.40-1.20 (m, 21H), 1.07 (d, 3H,
J ) 7.2 Hz), 0.91 (t, 3H, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3)
δ 177.5, 171.0, 153.1, 103.8, 96.6, 86.5, 85.4, 84.2, 78.9, 74.0,
72.9, 70.7, 69.3, 66.1, 65.1, 49.4, 45.6, 44.6, 42.2, 41.7, 40.4,
35.1, 29.1, 25.9, 22.6, 22.3, 21.6, 21.2, 17.9, 16.7, 16.3, 14.9,
10.2, 9.9; MS (FAB) m/z 775 (M+ + H), 617, 158; HRFABMS
calcd for C38H67N2O14 (M+ + H) m/z 775.4592, found m/z
775.4587.
6-Deoxy-6,9-ep oxy-6-(2-h yd r oxy-2-m et h ylp r op yl)-7,8-
n or -11-O-a cetyler yth r om ycin A (20). Compound 20 was
prepared from 19 in 92% yield as a colorless foam by the same
procedure as 13a : IR νmax (CHCl3) 3471, 3015, 2978, 1732,
1
1602, 1456, 1382 cm-1; H NMR (300 MHz, CDCl3) δ 5.30 (d,
1H, J ) 10.5 Hz), 4.85 (dd, 1H, J ) 10.8 Hz, 2.4 Hz), 4.66-
4.59 (m, 2H), 4.30 (d, 1H, J ) 5.7 Hz), 4.28 (bs, 1H), 3.97 (m,
1H), 3.60 (m, 1H), 3.34 (s, 3H), 3.20 (dd, 1H, J ) 10.5 Hz, 7.2
Hz), 3.10 (m, 2H), 2.66 (qd, 1H, J ) 7.2 Hz, 1.8 Hz), 2.46 (m,
1H), 2.4-2.2 (m, 2H), 2.29 (s, 6H), 2.10 (s, 3H), 1.88 (s, 3H),
1.78 (qd, J ) 7.5 Hz, 2.4 Hz), 1.73-1.50 (m, 4H), 1.40-1.30
(m, 9H), 1.28-1.12 (m, 16H), 0.88 (t, 3H, J ) 7.2 Hz); 13C NMR
(75 MHz, CDCl3) δ 175.7, 174.6, 169.1, 101.5, 94.0, 89.6, 80.4,
79.6, 77.9, 75.6, 75.4, 73.1, 70.7, 70.1, 68.8, 65.5, 65.3, 49.2,
46.0, 43.2, 42.9, 42.3, 40.3, 34.5, 32.2, 31.2, 28.6, 24.0, 23.2,
21.7, 21.3, 20.7, 17.5, 15.7, 11.4, 11.3, 9.80; MS (FAB) m/z 806
(M+ + H); HRFABMS calcd for C40H72NO15 (M+ + H) m/z
806.4902, found m/z 806.4901.
8-(R)-3′-N-Dem et h yl-8a -oxa -2′-O,3′-N,4′′-O-t r is(b en z-
yloxyca r bon yl)-8a -h om oer yth r om ycin A (17). Compound
12a (100 mg, 0.086 mmol) was dissolved with THF (1 mL) and
cooled to -78 °C under N2 atmosphere. To this solution was
added slowly a THF solution of bis-Grignard reagent (0.44 M,
975 µL), prepared from dibromobutane and magnesium, and
the mixture stirred at -78 °C for 2 h and 50 min. After
consumption of 12a was confirmed by TLC, 10% HCl and
EtOAc were added into the reaction mixture, and the mixture
stirred at 0 °C for 20 min. The mixture was worked up in
EtOAc to yield a crude product. Purification by silica gel
chromatography (n-hexane:EtOAc ) 1:1) afforded 64 mg (65%)-
of 17 as a colorless foam. IR (CHCl3) νmax 3538, 3470, 2970,
2930, 1737, 1693, 1453, 1381, 1333 cm-1; 1H NMR (300 MHz,
CDCl3) δ 3.37, 2.95 (two s, 3H), 2.83, 2.79 (two s, 3H); 13C NMR
(75 MHz, CDCl3) δ 178.6, 178.5, 175.0, 156.6, 156.3, 155.6,
155.6, 154.7, 154.7, 136.8, 136.6, 135.6, 135.5, 135.5, 135.2,
128.7, 128.6, 128.5, 128.3, 128.2, 128.0, 99.6, 94.9, 94.9, 82.8,
82.6, 75.7, 75.2, 75.0, 72.5, 70.2, 69.8, 69.7, 69.6, 69.4, 67.4,
Su p p or tin g In for m a tion Ava ila ble: Photocopies of 1H
and 13C NMR spectra for 7, 9, 10, 11a , 11b, 12a , 12b, 14a ,
14b, 15a , 15b, 16a , 16b, 17, 18, 19, 20, which were not
analyzed, and crystal data and ORTEP for 13a and 13b. This
material is available free of charge via the Internet at
http://pubs.org.
J O020458E
9152 J . Org. Chem., Vol. 67, No. 26, 2002