An efficient entry to new sugar modified ketolide antibiotics

Article abstract of DOI:10.1016/j.tetlet.2005.01.023

A new and efficient route to a ketolide aglycon served as a basis for the unprecedented 5-O-glyco-modification of ketolide antibiotics. Combined with an effective copper-catalyzed triazole-forming reaction a series of novel and potent ketolide antibiotics

Full text of DOI:10.1016/j.tetlet.2005.01.023

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1483–1487
An efficient entry to new sugar modified ketolide antibiotics
Alex Romero, Chang-Hsing Liang, Yu-Hung Chiu, Sulan Yao, Jonathan Duffield,
Steven J. Sucheck, Ken Marby, David Rabuka, Po Yee Leung, Youe-Kong Shue,
Yoshi Ichikawa and Chan-Kou Hwang*
Department of Chemistry, Optimer Pharmaceuticals, Inc., 10110 Sorrento Valley Road, Suite C, San Diego, CA 92121, USA
Received 16 September 2004; revised 5 January 2005; accepted 7 January 2005
Available online 22 January 2005
Abstract—A new and efficient route to a ketolide aglycon served as a basis for the unprecedented 5-O-glyco-modification of ketolide
antibiotics. Combined with an effective copper-catalyzed triazole-forming reaction a series of novel and potent ketolide antibiotics
were synthesized.
Ó 2005 Elsevier Ltd. All rights reserved.
Macrolide antibiotics, including erythromycin A (1),
clarithromycin (2), and azithromycin (3) (Fig. 1), are
important therapeutic agents for the treatment of respi-
ratory tract infections (RTIs) due to their broad spec-
trum of activity against several dominant respiratory
pathogens and their excellent safety profile. However,
the widespread use of antibiotics over the past decades
has increased the prevalence of macrolide antibiotic-
resistant pathogens. It is estimated that by this year,
nearly 40% of all Streptococcus strains, the major
causative pathogen for RTIs, will be resistant to both
penicillin and macrolide antibiotics in the US.1
Their structural features are: (1) lack of 3-O-cladinose,
(2) presence of 3-keto group, and (3) presence of aro-
matic functionality to interact with domain II of the
bacterial rRNA, as seen in telithromycin (4).2 Although
ketolides demonstrate excellent antibacterial activities,
they are still prone to ubiquitous resistance mechanisms
developed by bacteria; Erm-mediated methylation of the
bacterial ribosomal RNA whereby the 5-O-desosamine
plays a key role.3,4a–c
We initiated our macrolide discovery program based on
the hypothesis that if we could establish a technology by
which the 5-O-desosamine residue of a ketolide can be
replaced with an optimized sugar motif, effective macro-
lide-based antibiotics could be discovered that are active
against these resistant pathogens. We embarked on
developing conditions for the following chemical trans-
formations: (1) an efficient procedure for aglycon prep-
aration, (2) facile glycosylation of the 5-OH group,
and (3) effective procedure for introducing aromatic
functionality for interacting with domain II.
Ketolides, a new class of macrolides, have recently been
developed having improved antibacterial activities.
N
N
N
NMe
O
NMe
O
2
R
O
2
O
N
HO
O
NMe2
O
HO
O
OH
O
HO
O
HO
HO
HO
HO
O
O
N
O
O
O
O
O
O
O
The 5-O-desosamine residue has been considered to be
critical for the antibacterial activity of macrolide/keto-
lide antibiotics and there have been only few reports
describing the removal or modification of this sugar.4,5
Attempted forcing acidic conditions to remove the 5-
O-desosamine commonly results in elimination side
products or decomposition of the macrolide core. For
example, when ketolide 5 was submitted to HCl in
MeOH or BF3ÆOEt2 in CH2Cl2, ketolide 6 was the only
identifiable side product isolated (Scheme 1). Due to the
acid sensitivity of the ketolide core and the difficulty
OH
OMe
OH
OMe
O
O
O
O
O
Azithromycin (3)
Erythromycin A (1) (R = H)
Clarithromycin (2) (R = Me)
Telithromycin (4)
Figure 1. Macrolide and ketolide antibiotics.
Keywords: Ketolide aglycon; Glycosylation; Triazole formation;
Antibiotics.
*
Corresponding author. Tel.: +1 858 909 0736; fax: +1 858 909
0737; e-mail: jhwang@optimerpharma.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.023

1484
A. Romero et al. / Tetrahedron Letters 46 (2005) 1483–1487
N3
N3
3-O-cladinose residue was accomplished using 1 N HCl
to give compound 9 in 92% yield. The resulting
3-OH group was oxidized using Swern conditions8 to
give the ketolide and then treated with MeOH to afford
5.
NMe2
O
O
HO
OMe
OMe
O
N
O
N
O
O
O
O
+
Decompostion
O
HCl, MeOH
or
O
O
O
BF3 OEt2, CH2Cl2
O
5
O
6
Ketolide 5 was subjected again to Swern oxidation.
Although we had confirmed that the reaction took place
by observing an additional carbonyl signal in the 13C
NMR spectrum, surprisingly, we were unable to isolate
10 in pure form by a silica gel chromatography due to
gradual degradation to the expected ketolide aglycon
product. Indeed, upon heating 10 in MeOH in the pres-
ence of silica gel generated ketolide aglycon 11 in 55%.
The structure of 11 was further confirmed by X-ray crys-
tallography.9 To our delight, we have also found that
the one-step bis-Swern oxidation of the diol derivative
(deacetylated product of 9), following methanolysis in
silica gel, also effectively afforded the ketolide aglycon
11.10
Scheme 1. Attempted acidic removal of 5-O-desosamine.
associated with removing the 5-O-desosamine sugar
from macrolide antibiotics, we focused on developing
a new procedure for the efficient removal of the 5-O-des-
osamine from ketolide derivatives. By identifying the
unique structural features of desosamine, namely, the
30-dimethylamino-20-hydroxy sugar motif (I) (Scheme
2), we speculated that the oxidation of the 20-OH group
to the 20-keto group (II) would facilitate tautomeriza-
tion to generate the 20,30-enol form (III). Subsequent
elimination of the glycoside under mild acidic hydrolysis
would then generate the desired ketolide aglycon (IV).
In order to initiate this investigation, we prepared the
versatile azide containing synthetic intermediate 5
(Scheme 3), which could be easily transformed into a
substituted-triazole containing ketolide, via a [3+2]
cycloaddition reaction between an azide and an alkyne.
The glycosylation of 11 with sugar derivative 12a–c
(Scheme 4) using NIS/AgOTf afforded the protected gly-
cosylated products 13a–c in 65–70% yield in ꢀ10:1 ano-
meric mixture in which the desired b-form was the
predominant isomer.11,12 The Fmoc protecting group
was removed by treating with 10% piperidine in DMF
and reductive amination was accomplished with NaB-
H(OAc)3 and formaldehyde in THF to give the requisite
N,N-dimethylamine. The glycosylated products having
the 20-OBz and/or 40-OBz groups were selectively re-
moved by heating in MeOH to give the deprotected ad-
ducts 14a–c in 65–75% yield for the combined three
steps. For each of the glycosylated deprotected ketol-
ides, the azide group was reacted with 2-pyridyl acety-
The synthesis of 5 began with the reaction of the known
acylimidazole intermediate 76 with 4-amino-1-butanol in
DMF to generate a cyclic carbamate (Scheme 3). As
previously described,7 the reaction of 7 with amines is
selective and produces a major isomer. Tosylation
of the primary alcohol and subsequent displacement of
the tosylate group with NaN3 in DMF afforded azido-
macrolide 8 in 88% overall yield. Removal of the
+NMe2
NMe2
NMe2
H
NMe2
H+
HO
HO
ROH
(Aglycon)
O
[O]
HO
RO
+
O
O
O
RO
H+
RO
O
I
II
III
IV
V
Scheme 2. Proposed mechanism for deglycosylation.
Scheme 3. Reagents and conditions: (a) 4-amino-1-butanol, DMF, 95%; (b) TsCl, pyridine, 93%; (c) NaN3, DMF, 80 °C, 100%; (d) 1 N HCl, MeOH,
92%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 °C to rt, 95%; (f) MeOH, 65 °C, 98%; (g) silica gel, MeOH, N2, 65 °C, 55%.

A. Romero et al. / Tetrahedron Letters 46 (2005) 1483–1487
1485
N3
N3
R2
O
R2
O
R1
OMe
R1
OMe
O
O
R3
R4
R3
R4
N
O
e
b, c, d
N
O
12a-12c
a
16, 17, 18
O
11
O
O
O
O
O
O
N
15
O
O
O
14a (R1=OH, R2=NMe2, R3=OH, R4= H)
14b (R1=OH, R2=NMe2, R3=OH, R4=OBz)
14c (R1=OH, R2=NMe2, R3=H, R4=OBz)
13a (R1=OBz, R2=NHFmoc, R3=OBz, R4= H)
13b (R1=OBz, R2=NHFmoc, R3=OBz, R4=OBz)
13c (R1=OBz, R2=NHFmoc, R3=H, R4=OBz)
N
N
N
NHFmoc
N
NHFmoc
OBz
NHFmoc
OBz
BzO
TolS
BzO
TolS
BzO
TolS
NMe2
O
HO
OMe
p-tolyl-glycosides
=
e
5
O
O
N
O
O
O
O
O
OBz
OBz
12a
12c
N
15
12b
O
O
O
19
Scheme 4. Reagent and conditions: (a) NIS, AgOTf, 2,6-di-tert-butylpyridine, 65%; (b) 10% piperidine, 83%; (c) HCHO, NaBH(OAc)3, 85%; (d)
MeOH, 70 °C, 92%; (e) cat. CuI, toluene, 75 °C, 98%.
N
N
N
N
N
N
N
N
N
N
N
N
NMe2
OH
NMe2
O
NMe2
OH
O
HO
OMe
HO
OMe
O
O
HO
OMe
N
O
N
O
N
O
O
O
O
O
O
O
O
O
OBz
OBz
O
O
O
O
O
O
O
16
O
O
17
18
Figure 2. Newly synthesized ketolides.14–19
lene 15 in the presence of catalytic amount of CuI to give
a single regioisomer of the triazole adducts, 16, 17, and
18 in >95% yield.13 Similarly, ketolide 5 was converted
to 19, having the natural 5-O-desosamine, in 98% yield.
Employing this strategy, novel ketolide antibiotics con-
taining new 5-O-sugars and having a unique hetero-aro-
matic triazole substituent were assembled (Fig. 2) and
tested for antimicrobial activity. Ketolides 17 and 18
were active against sensitive S. pneumoniae (ATCC
49619) (both <0.125 lg/mL) and macrolide resistant S.
pyogenes (3029, erm) (2 and 0.5 lg/mL, respectively).
Ketolide 16 and 19, containing the naturally occurring
sugars, mycaminose and desosamine, respectively, were
active against S. pneumoniae (both <0.125 lg/mL),
although they were devoid of activity against S.
pyogenes (3029, erm) (both >64 lg/mL). From this
initial screening, we have identified ketolides having
the novel 5-O-sugar motif containing an additional 60-
OBz group (17 and 18) exhibited excellent antibacterial
activities. The results of these microbiological studies
will be reported elsewhere.
Acknowledgements
This work was partially supported by SBIR research
grant 1R43 AI058395-01, awarded by the National
Institute of Allergy and Infectious Diseases, National
Institute of Health. We thank Dr. Pamela Sears, Mrs.
Niki Robert, and Mrs. Jamie Seddon for the biological
evaluation of these compounds. We also thank Profes-
sors Chi-Huey Wong, Samuel J. Danishefsky, and K.
Barry Sharpless for helpful discussions.
References and notes
1. McCormick, A. W.; Whitney, C. G.; Farley, M. M.;
Lynfield, R.; Harrison, L. H.; Bennet, N. M.; Schaffner,
W.; Reingold, A.; Hadler, J.; Cieslak, P.; Samore, M. H.;
Lipsitch, M. Nat. Med. 2003, 1–7.
2. Agouridas, C.; Chantot, J.-F.; Denis, A.; Solange, G. D.;
Odile, L. M. U.S. Patent 5,635,485, 1997.
3. Schmitz, F.-J.; Petridou, J.; Jagusch, H.; Astfalk, N.;
Scheuring, S.; Schwarz, S. J. Antimicrob. Chemother. 2002,
49, 611–617.
4. (a) Omura, S. Macrolide Antibiotics Chemistry, Biology,
and Practice; Academic: London, 2002; (b) Zhanel, G.
G.; Walters, M.; Noreddin, A.; Vercaigne, L. M.;
Wierzbowski, A.; Embil, J. M.; Gin, A. S.; Douthwaite,
S.; Hoban, D. J. Drugs 2002, 62, 1771–1804; (c) Asaka,
T.; Manaka, A.; Sugiyama, H. Curr. Top. Med. Chem.
In summary, mild conditions for preparing ketolide
aglycons have been developed, which served as a
basis for the unprecedented 5-O-glyco-modification of
ketolide antibiotics. This work may provide
significant opportunities for the design of a new class
of macrolide/ketolide-based antibiotics.

1486
A. Romero et al. / Tetrahedron Letters 46 (2005) 1483–1487
2003, 3, 961–989; (d) Jones, P. H.; Powley, E. K. J. Org.
1H), 8.17 (s, 1H), 8.16 (ddd, J = 7.6, 1.3, 0.8 Hz, 1H), 7.77
(ddd, J = 7.6, 7.6, 1.3, Hz, 1H), 7.21 (ddd, J = 7.6, 4.8,
1.3 Hz, 1H), 4.94 (dd, J = 10.7, 2.4 Hz, 1H), 4.46 (t,
J = 7.3 Hz, 2H), 4.33 (d, J = 7.3 Hz, 1H), 4.26 (d,
J = 8.3 Hz, 1H), 3.83 (q, J = 6.8 Hz, 1H), 3.79–3.56 (m,
3H), 3.46 (dd, J = 10.4, 7.4 Hz, 1H), 3.39–3.30 (m, 1H),
3.18–3.02 (m, 3H), 2.62 (s, 3H), 3.65–2.58 (m, 1H), 2.51 (s,
6H), 2.37 (dd, J = 10.4, 9.9 Hz, 1H), 2.11–1.50 (m, 8H),
1.35 (d, J = 6.8 Hz, 3H), 1.32 (d, J = 7.6 Hz, 3H), 1.31 (s,
3H), 1.25 (s, 3H), 1.24 (d, J = 7.6 Hz, 3H), 1.17 (d,
J = 7.1 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H), 0.85 (t,
J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 216.0,
203.6, 169.9, 157.5, 150.7, 149.6, 148.5, 137.0, 122.9, 122.2,
120.4, 103.6, 82.4, 79.3, 78.3, 78.0, 73.6, 71.3, 70.4, 66.7,
60.6, 51.4, 50.2, 50.1, 47.2, 45.0, 42.9, 41.9, 39.7, 39.3, 28.0,
24.4, 22.5, 19.9, 18.6, 18.06, 15.7, 14.9, 14.8, 14.2, 10.7.
MS: Calcd for C42H65N6O11 (M+H): 829.5, found: 829.4.
17. Spectroscopic data for compound 17: 1H NMR
(400 MHz, CDCl3): d 8.57 (ddd, J = 4.9, 1.8, 0.9 Hz,
1H), 8.18 (s, 1H), 8.19–8.15 (m, 1H), 8.10–8.00 (m, 2H),
7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.61–7.55 (m, 1H), 7.49–7.43
(m, 2H), 7.21 (ddd, J = 7.6, 4.8, 1.3 Hz, 1H), 4.93 (dd,
J = 10.6, 2.3 Hz, 1H), 4.68 (dd, J = 11.9, 5.8 Hz, 1H), 4.56
(dd, J = 11.9, 2.5 Hz, 1H), 4.49–4.40 (m, 3H), 4.29 (d,
J = 8.1 Hz, 1H), 3.84 (q, J = 6.8 Hz, 1H), 3.76–3.54 (m,
4H), 3.46–3.36 (m, 2H), 3.13–3.04 (m, 2H), 2.58–2.51 (m,
1H), 2.51 (s, 6H), 2.48 (s, 3H), 2.47 (dd, J = 10.1, 10.1 Hz,
1H), 2.03–1.41 (m, 8H), 1.47 (s, 3H), 1.35 (d, J = 6.8 Hz,
3H), 1.27 (d, J = 7.0 Hz, 3H), 1.26 (s, 3H), 1.14 (d,
J = 7.1 Hz, 3H), 1.00 (d, J = 7.1 Hz, 3H), 0.85 (t,
J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 215.82,
203.49, 169.90, 167.05, 157.25, 150.40. 149.34, 148.30,
136.84, 133.46, 129.78, 129.68, 128.55, 122.71, 122.00,
120.21, 103.44, 82.21, 77.93, 77.47, 76.71, 75.77, 70.37,
70.14, 66.24, 63.94, 60.39, 51.19, 49.93, 49.58, 46.87, 44.83,
42.62, 41.70, 39.36, 38.97, 27.70, 24.19, 22.63, 19.65, 18.39,
15.42, 14.65, 14.41, 13.94, 10.43. HRMS (ES): Calcd for
C49H69N6O13 (M+H): 949.4917, found: 949.4902.
Chem. 1968, 33, 665–670; (e) LeMahieu, R. A.; Carson,
M.; Kierstead, R. W. J. Med. Chem. 1974, 17, 953–956.
5. Djokic, S.; Kobrehel, G.; Lazarevski, G.; Lopotar, N.;
Tamburasev, Z. J. Chem. Soc., Perkin Trans. 1 1986, 1881.
6. Baker, W. R.; Clark, J. D. U.S. Patent 4,742,049, 1988.
7. Or, Y.; Clark, R.; Wang, S.; Chu, D.; Nilius, A.; Flamm,
R.; Mitten, M.; Ewing, P.; Alder, J.; Ma, Z. J. Med. Chem.
2000, 43, 1045–1049.
8. Swern, D. J. Org. Chem. 1976, 41, 957–962.
9. Crystallographic data for structure 11 in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
250316.
10. We have applied this procedure (Swern oxidation then
methanolysis) to telithromycin. The telithromycin aglycon
was successfully obtained in 55% yield.
11. The p-tolyl glycosides were designed and synthesized in-
house. The protecting group scheme (i.e., 2-OBz) was
chosen in order to direct the b-configuration at the
anomeric center resulting from the glycosylation reaction.
12. General procedure for the glycosylation of aglycon 11: N-
Iodosuccinimide (1.5 equiv) was added to a mixture of 11-
N-(4-azido-butyl)-6-O-methyl-5-hydroxy-3-oxo-erythron-
olide A, 11,12-carbamate 11 (1.0 equiv, 1 mmol), thiogly-
coside (1.3 equiv), molecular sieves (250 mg), and CH2Cl2
(10 mL) at ꢁ78 °C. After 10 min, AgOTf (1.7 equiv) and
2,6-di-tert-butyl-pyridine (1.8 equiv) were added and the
mixture was gradually allowed to warm to rt. After 6–
18 h, a 1:1 mixture of satd aq NaHCO3 and Na2SO3
(50 mL) was added and the mixture was diluted with
CH2Cl2 (150 mL) and the resulting layers were separated.
The organic layer was dried with Na2SO4 and concen-
trated. Purification by silica gel chromatography (toluene–
acetone) afforded glycosylated compounds.
13. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, B. Angew. Chem., Int. Ed. 2002, 114, 2596–
2599; (b) Tornoe, C. W.; Christensen, C.; Meldal, M. J.
Org. Chem. 2002, 67, 3057–3064.
18. Spectroscopic data for compound 18: 1H NMR
(400 MHz, CDCl3): d 8.59 (dd, J = 4.8, 1.8 Hz, 1H), 8.18
(s, 1H), 8.17 (dd, J = 7.6, 1.0 Hz, 1H), 8.08 (dd, J = 8.0,
1.3 Hz, 2H), 7.78 (ddd, J = 7.6, 7.6, 1.8 Hz, 1H), 7.59 (tt,
J = 7.3, 1.3 Hz, 1H), 7.47 (dd, J = 8.0, 7.3 Hz, 2H), 7.22
(ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 4.95 (dd, J = 10.5, 2.0 Hz,
1H), 4.47 (t, J = 7.4 Hz, 2H), 4.39 (m, 3H), 4.27 (d,
J = 8.3 Hz, 1H), 3.86 (q, J = 6.8 Hz, 1H), 3.78–3.63 (m,
4H), 3.57 (s, 1H), 3.28 (dd, J = 10.0, 7.1 Hz, 1H), 3.19–
3.05 (m, 2H), 2.60–2.50 (m, 2H), 2.47 (s, 3H), 2.32 (s, 6H),
2.05–1.52 (m, 10H), 1.49 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H)
1.32 (d, J = 7.3 Hz, 3H), 1.28 (s, 3H), 1.16 (d, J = 6.8 Hz,
3H) 1.02 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d 216.2, 203.8, 169.9, 166.5,
157.5, 150.7, 149.6, 148.6, 137.0, 133.6, 129.9, 129.8, 128.7,
122.9, 122.2, 120.4, 104.2, 82.4, 79.8, 78.2, 77.4, 71.8, 70.5,
66.5, 65.9, 60.6, 51.4, 50.2, 49.7, 47.5, 45.1, 42.8, 40.4, 39.6,
39.2, 27.9, 24.4, 23.1, 22.4, 20.0, 18.6, 15.8, 14.8, 14.5, 14.1,
10.7. MS: Calcd for C49H69N6O12 (M+H): 933.5, found:
933.4.
14. Spectroscopic data for compound 6: 1H NMR (400 MHz,
CDCl3): d 4.52 (dd, J = 7.9, 4.2 Hz, 1H), 4.07–4.04 (m,
1H), 3.85 (q, J = 6.8 Hz, 1H), 3.70–3.61 (m, 1H), 3.47–3.38
(m, 3H), 3.22 (s, 3H), 3.09–3.00 (m, 2H), 4.30 (dq,
J = 10.5, 7.0 Hz, 1H), 2.15 (d, J = 17.9 Hz, 1H), 2.03 (d,
J = 17.9 Hz, 1H), 1.90–1.79 (m, 1H), 1.62 (s, 3H), 1.73–
1.48 (m, 4H), 1.33 (d, J = 7.0 Hz, 3H), 1.33 (s, 3H), 1.30
(d, J = 6.6 Hz, 3H), 1.26 (s, 3H), 1.28–1.24 (m, 1H), 1.12
(d, J = 7.1 Hz, 3H), 0.97 (t, J = 7.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 206.04, 168.76, 157.56, 148.75,
102.38, 83.67, 78.79, 77.91, 72.31, 60.13, 51.19, 50.79,
49.05, 47.67, 45.69, 38.02, 36.68, 26.57, 24.37, 23.18, 22.84,
17.50, 17.23, 14.99, 14.76, 11.37, 9.65. MS: Calcd for
C27H42N4O7Na (M+Na): 557.30, found: 557.22.
15. Spectroscopic data for compound 11: 1H NMR
(400 MHz, CDCl3): d 4.93 (dd, J = 10.5, 2.3 Hz, 1H),
4.20 (d, J = 9.4 Hz, 1H), 3.84 (q, J = 7.0 Hz, 1H), 3.72–
3.61 (m, 2H), 3.59 (s, 1H), 3.38–3.28 (m, 2H), 3.15 (q,
J = 7.0 Hz, 1H), 2.91 (m, 1H), 2.71 (s, 3H), 2.67–2.62 (m,
1H), 1.97 (ddt, J = 7.6, 5.3, 2.3 Hz, 1H), 1.80 (dd, J = 14.6,
2.6 Hz, 1H), 1.70–1.52 (m, 6H), 1.50 (s, 3H), 1.41 (d,
J = 7.0 Hz, 3H), 1.39 (s, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.16
(d, J = 7.0 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 0.88 (t,
J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 216.1,
203.8, 169.3, 157.2, 82.2, 78.4, 77.2, 74.3, 60.3, 51.6, 51.0,
49.7, 47.1, 44.7, 42.9, 39.1, 38.3, 26.2, 24.3, 22.2, 19.9, 18.2,
16.7, 14.7, 14.4, 13.8, 10.4. HRMS (ES): Calcd for
C27H45N4O8 (M+H): 553.3232, found: 553.3222.
19. Spectroscopic data for compound 19: 1H NMR
(400 MHz, CDCl3): d 8.57 (ddd, J = 4.8, 1.8, 1.0 Hz,
1H), 8.17 (s, 1H), 8.16 (ddd, J = 7.8, 1.3, 1.0 Hz, 1H), 7.77
(ddd, J = 7.8, 7.6, 1.8 Hz, 1H), 7.21 (ddd, J = 7.6, 4.8,
1.3 Hz, 1H), 4.93 (dd, J = 10.6, 2.3 Hz, 1H), 4.46 (t,
J = 7.6 Hz, 2H), 4.30 (d, J = 7.3 Hz, 1H), 4.23 (d,
J = 8.8 Hz, 1H), 3.84 (q, J = 6.8 Hz, 1H), 3.81–3.53 (m,
3H), 3.57 (s, 1H), 3.31–3.23 (m, 1H), 3.16–3.02 (m, 2H),
2.95–2.90 (m, 1H), 2.78 (s, 1H, –OH), 2.62 (s, 3H), 2.63–
2.56 (m, 1H), 2.37 (s, 6H), 2.10–1.50 (m, 10H), 1.47 (s,
3H), 1.35 (d, J = 6.8 Hz, 3H), 1.33 (s, 3H), 1.29 (d,
16. Spectroscopic data for compound 16: 1H NMR
(400 MHz, CDCl3): d 8.57 (ddd, J = 4.8, 1.3, 0.8 Hz,

A. Romero et al. / Tetrahedron Letters 46 (2005) 1483–1487
1487
J = 7.6 Hz, 3H), 1.27 (d, J = 6.0 Hz, 3H), 1.16 (d,
J = 7.1 Hz, 3H), 1.01 (d, J = 7.1 Hz, 3H), 0.86 (t,
J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 215.6,
203.7, 169.7, 157.3, 150.1, 149.3, 148.3, 136.8, 122.7, 122.0,
120.2, 103.9, 82.2, 79.7, 78.2, 76.7, 70.3, 69.6, 65.9, 60.4,
51.2, 50.0, 49.9, 47.6, 44.9, 42.7, 40.2, 39.6, 39.0, 28.2, 27.7,
24.2, 22.2, 21.2, 19.8, 18.4, 15.8, 14.7, 14.4, 13.9, 10.5. MS:
Calcd for C42H65N6O10 (M+H):813.48, found: 813.48.