Studies towards the total synthesis of narbonolide: stereoselective preparation of the C1-C10 fragment

Article abstract of DOI:10.1016/j.tetlet.2008.02.099

An efficient stereoselective synthesis of the C1-C10 fragment of narbonolide is reported. The stereocentres at C2, 3, 4, 5, 8 and 9 in fragment 5 can be generated via an iterative asymmetric acyl-thiazolidinethione aldol reaction, whereas the stereocentre

Full text of DOI:10.1016/j.tetlet.2008.02.099

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Tetrahedron Letters 49 (2008) 3185–3188
Studies towards the total synthesis of narbonolide:
stereoselective preparation of the C1–C10 fragment q
C. Prasad Narasimhulu a,b, Javed Iqbal a, Khagga Mukkanti b, Parthasarathi Das a,*
a Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
b Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 085, AP, India
Received 10 December 2007; revised 15 February 2008; accepted 16 February 2008
Available online 21 February 2008
Abstract
An efficient stereoselective synthesis of the C1–C10 fragment of narbonolide is reported. The stereocentres at C2, 3, 4, 5, 8 and 9 in
fragment 5 can be generated via an iterative asymmetric acyl-thiazolidinethione aldol reaction, whereas the stereocentre at C6 is installed
by means of Myers alkylation.
Ó 2008 Elsevier Ltd. All rights reserved.
Ketolides1 are a new class of macrolide antibiotics that
N
have been shown to be active against a variety of bacteria
including macrolide-resistant bacteria and mycobacteria.
N
Ketolides differ from erythromycin A by harbouring a
N
3-keto group instead of a L-cladinose group. The 3-ketone
modification has imparted this class of compounds with
excellent activities against drug resistant bacterial infec-
tions especially the clinically important respiratory tract
pathogen Streptococcus pneumoniae.2
N
O
O
O
O
H
N
N
O
O
O
O
OH
OH
The therapeutic promise shown by ketolides has led to a
resurgence in macrolide antibiotic research in the pharma-
ceutical industry,3 with successful clinical candidates such
as telithromycin4a (1) from Aventis Pharma, and cethromy-
cin (2) from Abbott Laboratories4b,c (Fig. 1).
Narbonolide 3 is a 14-membered polyketide macrolac-
tone biosynthesized by the pikromycin polyketide synthase
(PKS) system of Streptomyces venezuelae ATCC 15439.5
Macrolide 3 consists of seven stereocentres including the
sensitive chiral centre at C2. Its significant therapeutic
potential, and structural similarity to the macrocytes in
O
O
N
O
O
N
O
O
O
O
O
O
cethromycin 2
telithromycin 1
Fig. 1.
telithromycin and cethromycin have resulted in total
syntheses from the groups of Masamune6a and Fecik.6b,c
However, these syntheses have one or more complicating
factors such as a low yield of the key macrocyclization
reaction, inability to differentiate the C3 and C5 positions
for chemoselective reactions and highly optimized protect-
ing group strategies that decrease the synthetic efficiency.
In considering an alternate strategy for the synthesis of
narbonolide and its structural analogues, we envisaged that
q
DRL Publication No. 670.
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304 5438.
*
E-mail addresses: parthasarathi@drreddys.com, parthads@yahoo.com
(P. Das).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.099

3186
C. Prasad Narasimhulu et al. / Tetrahedron Letters 49 (2008) 3185–3188
O
O
9
good yield. Reductive removal of the chiral auxiliary from
thione 9 with LiBH4 and subsequent iodination of the
resulting alcohol 10 yielded iodide 11. Iodide 11 was then
subjected to Myers alkylation11conditions. Treatment of
iodide 11 with (R,R)-pseudoephedrine propionate 12 at
40 °C proceeded cleanly to furnish amide 13 in 77% yield.
Removal of the chiral auxiliary was accomplished with
lithium amidotrihydroborate12 to produce alcohol 14,13
which was further oxidized to aldehyde 15, in the presence
of TEMPO and iodosobenzene diacetate (Scheme 2).
Aldolization of aldehyde 15 with N-propionyl thiazoli-
dinethione 7 gave the non-Evans syn aldol product 16 via
the Crimmins protocol (titanium mediated enolization
using 1 equiv of diisopropylethylamine as base).8a The
reaction was readily scalable, providing reproducible
results in terms of both yield and diastereoselectivity
(20:1). Reductive removal of the thiazolidinethione of 16
with NaBH4 produced diol 17. The 1,3-diol in 17 was then
protected with 4-methoxybenzaldehyde dimethylacetal
affording the corresponding acetal 18 which after reductive
hydrolysis with DIBAL-H afforded primary alcohol 19 in
good yield.14 The resulting alcohol was oxidized to the
corresponding aldehyde 20 and subjected to aldol reaction
with thiazolidinethione 7 to give non-Evans syn aldol
adduct 21 in 83% yield and excellent diastereoselectivity
(P96%).8 The aldol product was silylated to give 22, which
on subsequent oxidative hydrolysis afforded C1–C10 frag-
ment 515 with all the required stereocentres (Scheme 3).
In summary, an efficient route for the synthesis of the
C1–C10 fragment of narbonolide has been developed,
which features aldol reactions to afford both Evans and
non-Evans syn aldol products from thiazolidinethione 7,
and Myers alkylation as key steps. Studies towards the
total synthesis of narbonolide and its structural analogues
for biological studies are currently underway in our
laboratory.
11
5
13
O
O
OR``
OR`
OH
1
3
O
O
O
Narbonolide 3
4
OR`
10
11
+
O
1
OR``
OR`
OR`
14
RO
6
5
Scheme 1.
the core structure of narbonolide 3 could be constructed
via ring closing metathesis of the bis olefin 4, which in turn
could be made via esterification of the C1–C10 fragment 5
and C11–O14 fragment 6. The stereocentres at C2, 3, 4, 5, 8
and 9 in fragment 5 can be generated via iterative asymmet-
ric acyl-thiazolidinethione aldol reactions, whereas the ste-
reocentre at C6 can be installed by means of Myers
alkylation (Scheme 1). Herein, we report the stereoselective
synthesis of the C1–C10 fragment of narbonolide.
Accordingly, our synthesis began with the aldolization
of N-propionyl thiazolidinethione7 7 with acrolein utilizing
the Crimmins protocol8,9 (titanium mediated enolization
using (ꢀ)-sparteine (1 equiv) and N-methyl-2-pyrrolidi-
none (1 equiv)) to yield the desired Evans syn aldol product
810 in 80% with excellent diastereoselectivity (20:1). Silyl-
ation of the aldol product 8 with TBSOTf afforded 9 in
S
S
S
O
OTBS
O
O
OH
b
a
c
S
N
S
N
S
N
Bn
Bn
Bn
8
9
7
O
N
OTBS
OTBS
OTBS
e
d
Ph
HO
I
OH
13
10
11
O
OTBS
O
OTBS
Ph
g
f
N
HO
OH
12
15
14
Scheme 2. Reagents and conditions: (a) TiCl4, (ꢀ)-sparteine, NMP, acrolein, CH2Cl2, ꢀ78 °C to 0 °C, 80% (20:1); (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C,
i
i
85%; (c) LiBH4, Et2O, H2O, rt, 76%; (d) PPh3, I2, imidazole, Et2O: CH3CN (4:1), rt, 79%; (e) 12, Pr2NH, n-BuLi, THF, 77%; (f) Pr2NH, n-BuLi,
BH3NH3, THF, 90%; (g) TEMPO, iodosobenzene diacetate, CH2Cl2, rt, 95%.

C. Prasad Narasimhulu et al. / Tetrahedron Letters 49 (2008) 3185–3188
3187
S
O
OH
OTBS
OH
OTBS
b
c
a
S
N
HO
15
Bn
17
16
PMP
O
OMPM
OTBS
O
OTBS
O
OMPM
OTBS
OTBS
e
d
HO
20
18
19
S
O
OH OMPM
OTBS
S
S
O
OTBSOMPM
f
g
N
N
S
Bn
Bn
21
22
O
OTBSOMPM
OTBS
h
HO
5
Scheme 3. Reagents and conditions: (a) 7, TiCl4, iPr2NEt, CH2Cl2, 0 °C, 74% (20:1); (b) NaBH4, EtOH, rt, 81%; (c) (OMe)2CHC6H4OMe, CSA, CH2Cl2,
i
rt, 92%; (d) DIBAL-H, CH2Cl2, 0 °C, 79%; (e) TEMPO, iodosobenzene diacetate, CH2Cl2, rt, 95%; (f) 7, TiCl4, Pr2NEt, CH2Cl2, 0 °C, 83% (24:1); (g)
i
TBSOTf, Pr2NEt, CH2Cl2, 0 °C to rt, 81%; (h) LiOH, 30% H2O2, THF:H2O, 0 °C, 65%.
A. J. Org. Chem. 2005, 70, 7267; (c) Venkatraman, L.; Salomon, C.
E.; Sherman, D. H.; Fecik, R. A. J. Org. Chem. 2006, 71, 9853.
Acknowledgements
7. (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J.
We thank Dr. Reddy’s Laboratories Ltd for financial
Chem. Soc., Chem. Commun. 1985, 1418; (b) Nagao, Y.; Hagiwara,
Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J.
support and encouragement. Help from the analytical
department in recording spectral data is appreciated.
Org. Chem. 1986, 51, 2391; (c) Romero-Ortega, M.; Colby, D. A.;
Olivo, H. F. Tetrahedron Lett. 2002, 43, 6439.
8. (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775; (b)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894; (c) Crimmins, M. T.; Caussanel, F. J. Am. Chem.
Soc. 2006, 128, 3128.
9. (a) Sai Baba, V.; Das, P.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett.
2006, 47, 7927; (b) Nyayavadi, V.; Nanduri, S.; Vasu Dev, R.; Naidu,
A.; Iqbal, J. Tetrahedron Lett. 2006, 47, 6667.
10. (a) Crimmins, M. T.; Christie, H. S.; Chaudhary, K.; Long, A. J. Am.
Chem. Soc. 2005, 127, 13810; (b) Crimmins, M. T.; Vanier, G. S. Org.
Lett. 2006, 8, 2887.
11. (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem.
Soc. 1994, 116, 9361; (b) Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc.
1997, 119, 6496.
References and notes
1. (a) Agouridas, C.; Denis, A.; Auger, J.-M.; Benedetti, Y.; Bonnefoy,
A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.; Fromentin, C.; D‘Ambr-
ieres, S. G.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.;
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Griesgraber, G.; Zhang, S.; Yong, H.; Phan, L. T.; Nemoto, P. A.;
Chu, D. T. W.; Plattner, J. J.; Zhang, X.; Zhong, P.; Cao, Z.;
Nilius, A. M.; Shortridge, V. D.; Flamm, R.; Mitten, M.;
Meulbroek, J.; Ewing, P.; Alder, J.; Or, Y. S. J. Med. Chem. 2001,
44, 4137.
3. Henninger, T. C. Expert Opin. Ther. Pat. 2003, 13, 787.
4. (a) Denis, A.; Agouridas, C.; Auger, J.-M.; Benedetti, Y.; Bonnefoy,
A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.; Fromentin, C.; D‘Ambr-
ieres, S. G.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.;
Tessot, N.; Pejac, J.-M.; Perron, S. Bioorg. Med. Chem. Lett. 1999, 9,
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M. A.; Condon, S. L.; Kerdesky, F. A. J.; King, S. A.; Peterson, M. J.;
Stoner, E. J.; Wittenberger, S. J. Cheminform 2005, 36, 10; (c)
Henninger, T. C.; Xu, X.; Abbanat, D.; Baum, E. Z.; Foleno, B. D.;
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37, 3623.
25
13. Spectral data of compound 14: ½aꢁD +16.4 (c 0.50, CHCl3); IR (neat):
3334, 2956, 2927, 1251, 1028, 837, 775 cmꢀ1 1H NMR (CDCl3,
;
400 MHz): d = 5.78 (ddd, J = 17.0, 10.5, 6.5 Hz, 1H), 5.12 (dd,
J = 17.0, 1.5 Hz, 1H), 5.08 (dd, J = 10.5, 1.5 Hz, 1H), 3.96–3.93 (m,
1H), 3.53 (dd, J = 10.5, 4.5 Hz, 1H), 3.39 (dd, J = 10.5, 6.5 Hz, 1H),
1.75–1.73 (m, 1H), 1.72–1.60 (m, 2H), 1.53–1.48 (m, 2H), 0.95 (d,
J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.87 (d, J = 7.0 Hz, 3H), 0.04 (s, 3H),
0.01 (s, 3H); 13C NMR (CDCl3, 50 MHz): d = 139.7, 114.8, 77.5, 67.8,
37.0, 35.9, 33.1, 25.9, 18.2, 17.9, 15.7, ꢀ4.3, ꢀ4.9; ESI-MS: m/z
(%) = 273 (100) [M+H]+; HRMS (ESI): [M+Na]+ calcd for
5. (a) Hori, T.; Maezawa, I.; Nagahama, N.; Suzuki, M. J. Chem. Soc.,
Chem. Commun. 1971, 304; (b) Maezawa, I.; Hori, T.; Kinumaki, A.;
Suzuki, M. J. Antibiot. 1973, 26, 771; (c) Xue, Y.; Zhao, L.; Liu,
H.-W.; Sherman, D. H. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 12111;
(d) Xue, Y.; Sherman, D. H. Metall. Eng. 2001, 3, 15.
C
15H32O2SiNa: 295.2071; found 295.2069.
14. Anderson, J. C.; McDermott, B. P.; Griffin, E. J. Tetrahedron 2000,
56, 8747.
25
15. Spectral data of compound 5: ½aꢁD +1.6 (c 1.00, CHCl3); IR (neat):
2954, 2929, 1707, 1514, 1249, 835, 775 cmꢀ1 1H NMR (CDCl3,
;
6. (a) Kaiho, T.; Masamune, S.; Toyoda, T. J. Org. Chem. 1982, 47,
1612; (b) Venkatraman, L.; Aldrich, C. C.; Sherman, D. H.; Fecik, R.
400 MHz): d = 7.26 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.74
(ddd, J = 17.0, 10.5, 6.5 Hz, 1H), 5.05 (dd, J = 17.0, 2.0 Hz, 1H), 5.00

3188
C. Prasad Narasimhulu et al. / Tetrahedron Letters 49 (2008) 3185–3188
(dd, J = 10.5, 1.2 Hz, 1H), 4.47 (d, J = 11.0 Hz, 1H), 4.36 (d,
NMR (CDCl3, 50 MHz): d = 179.2, 159.0, 140.1, 131.1, 129.0,
114.7, 113.6, 83.6, 76.4, 74.9, 73.1, 55.2, 43.0, 39.5, 37.5, 36.2, 33.6,
26.1, 25.9, 23.8, 20.8, 18.3, 16.9, 16.8, 11.2, 10.9, ꢀ4.0, ꢀ4.1, ꢀ4.2,
ꢀ4.8; ESI-MS: m/z (%) = 659 (100) [M+Na]+, 637 (95) [M+H]+;
HRMS (ESI): [M+H]+ calcd for C35H65O6Si2: 637. 0687; found 637.
0661.
J = 11.0 Hz, 1H), 4.02–3.99 (m, 1H), 3.90–3.88 (m, 1H), 3.73 (s,
3H), 3.14 (dd, J = 5.5, 3.5 Hz, 1H), 2.67 (dd, J = 7.0, 3.5 Hz, 1H),
2.02–1.98 (m, 1H), 1.83–1.80 (m, 1H), 1.68–1.61 (m, 4H), 1.13 (d,
J = 7.0 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H),
0.90 (s, 3H), 0.905 (s, 9H), 0.88 (s, 9H), 0.02 (s, 6H), 0.001 (s, 6H); 13
C