Asymmetric synthesis of the polyol subunit of the macrolide antibiotic, ossamycin

Article abstract of DOI:10.1016/j.tetlet.2005.06.079

An asymmetric synthesis of the C1-C16 polyol subunit of the macrolide antibiotic, ossamycin, has been achieved through stepwise carbon-chain elongation reaction from D-glucose.

Full text of DOI:10.1016/j.tetlet.2005.06.079

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5707–5709
Asymmetric synthesis of the polyol subunit of the
macrolide antibiotic, ossamycin
Noriki Kutsumura and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1,
Kohoku-ku, Yokohama 223-8522, Japan
Received 26 May 2005; revised 14 June 2005; accepted 16 June 2005
Available online 1 July 2005
Abstract—An asymmetric synthesis of the C1–C16 polyol subunit of the macrolide antibiotic, ossamycin, has been achieved through
stepwise carbon-chain elongation reaction from D-glucose.
Ó 2005 Elsevier Ltd. All rights reserved.
Ossamycin 1, isolated in 1965 from the culture broth of
Streptomyces sp.,1 is a member of such macrolide anti-
biotics, as cytovaricin,2 oligomycins,3 A82548A,4 and ruta-
mycins.5 This 24-membered macrolide inhibits oxidative
phosphorylation by targeting the mitochondrial F0F1
ATP synthase, and might be a promising candidate for
effective antitumor agents from recent biological exami-
nation.6 We initiated a synthetic study of 1 to understand
its chemical feature, and to develop an effective synthetic
methodology, which would make it possible to acquire re-
lated, more biologically effective substances. We describe
herein our synthetic process of the polyol subunit of 1.
Scheme 1. Retrosynthetic analysis.
Keywords: Ossamycin; Asymmetric synthesis; Macrolide; Antitumor.
*
Corresponding author. Tel./fax: +81 4556 61717; e-mail: nisiyama@chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.079

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N. Kutsumura, S. Nishiyama / Tetrahedron Letters 46 (2005) 5707–5709
As shown in Scheme 1, retrosynthetic analysis indicated
that the aglycone of ossamycin may be produced by
coupling between the polyol 3 and spiroketal subunits
4 via olefination and macrolactonization. The strategy
of the asymmetric synthesis of the polyol subunit 3
included stepwise carbon-chain elongation reaction of
methyl a-D-glucopyranoside 8, followed by asymmetric
dihydroxylation/epoxydation.
MeI, NaH; (iii) H2, Pd(OH)2–C; (iv) TsCl, pyr.; (v)
Ac2O, pyr.) to 16, the NOE experiments of which indi-
cated the configuration of the newly introduced stereo-
chemistry as depicted in Scheme 3. After selective
protection of the secondary alcohol of 6, the remaining
primary alcohol was submitted to oxidation, followed
by the Wittig reaction to afford 17.
In the next stage, we examined a simultaneous construc-
tion of the stereogenic centers at C4 and C5 positions of
17 (Scheme 4). Any efforts to achieve its asymmetric
The known branched-chain sugar 9,7 readily accessible
in seven steps from 8, was converted into 10 via zinc
reduction,8 and subsequent recyclization (Scheme 2).
After carbon-chain elongation of 10 by the Wittig reac-
tion with the phosphonium salt 12, furanoside 11 was
transformed into the acyclic aldehyde 7 in five steps.9
Construction of the stereogenic centers at the C6–C7
position was examined in the next stage (Scheme 3).
The carbon chain of 7 was elongated by the Wittig reac-
tion, followed by regioselective catalytic OsO4 dihydr-
oxylation10 to give 13 in 99% yield (two steps) with
good stereoselectivity (a 95:5 ratio was determined
1
by H NMR spectra). After LiBH4 reduction, the triol
generated was submitted to cyclic carbonate protection
and mesylation to afford 14. After removal of the cyclic
carbonate, the resulting diol was treated under basic
conditions to give the epoxy alcohol 15. Reaction of
15 with Me2Cu(CN)Li2 effected the predominant intro-
duction of a methyl group at the C2 position, leading
to 1,3-diol 6.11 To confirm the structure of 6, this com-
pound was converted in five steps ((i) TrCl, pyr.; (ii)
Scheme 4. Asymmetric induction at the C4–C5 position.
Scheme 2. Reagents and conditions: (a) (i) TsCl, pyr.; (ii) NaI/DMF; (iii) Zn powder/EtOH; (iv) Amberlyst 15E/MeOH, 65% in four steps.
(b) (i) 9-BBN/THF, then H2O2, NaOH/aq; (ii) (COCl)2, DMSO, Et3N/CH2Cl2; (iii) 12, nBuLi/THF; (iv) H2, 10% Pd–C/EtOH, 82% in four steps.
(c) (i) BF3ÆOEt2, Ac2O; (ii) K2CO3/MeOH; (iii) NaBH4/MeOH; (iv) TESOTf, 2,6-lutidine/CH2Cl2 dichloromethane; (v) (COCl)2, DMSO, then
Et3N/CH2Cl2, 90% in five steps.
Scheme 3. Reagents and conditions: (a) (i) Ph3P@CHCO2Me/benzene; (ii) OsO4, NMO/acetone–H2O (10:1), 99% in two steps. (b) (i) LiBH4/THF;
(ii) CO(Im)2/benzene; (iii) MsCl, DMAP, pyr., 81% in three steps. (c) NaOMe/MeOH, 95%. (d) Me2Cu(CN)Li2/Et2O, 87%. (e) (i) p-anisaldehyde
dimethyl acetal, PPTS/CH2Cl2; (ii) DIBAL-H/toluene, 64% in two steps; (iii) Dess–Martin periodinane, NaHCO3/CH2Cl2; (iv) Ph3P@C(Me)CO2Me/
benzene, 90% in two steps.

N. Kutsumura, S. Nishiyama / Tetrahedron Letters 46 (2005) 5707–5709
5709
Scheme 5. Reagents and conditions: (a) (i) LiBH4/THF; (ii) m-CPBA, NaHCO3/CH2Cl2, 70% in two steps; (iii) TPAP, NMO/CH2Cl2, 76%; (iv)
Ph3P@CHCO2Me/benzene, 100%. (b) (i) DDQ/CH2Cl2–H2O (20:1), 86%; (ii) dimetylcarbamyl chloride, NaH/DMF, 65%. (c) BF3ÆOEt2/CH2Cl2,
36%.
Kihara, T.; Isono, K. J. Antibiot. 1983, 36, 1263; (d)
Kihara, T.; Ubukata, M.; Uzawa, J.; Isono, K. J. Antibiot.
1989, 42, 919–925.
induction have been unsuccessful. For instance, a route
via asymmetric dihydroxylation provided insufficient re-
sults (no reaction by AD mix and a 3:1 mixture in 40%
yield by OsO4–Me3NO). An alternative route via asym-
metric epoxidation was ruled out, because of difficulties
in the following epoxide ring opening. As we considered
these results could be accounted for by steric hindrance
of the PMB group at the C7 position, subsequently its
removal was undertaken (Scheme 5). Thus, the carbon-
chain elongation of 17 was accomplished by LiBH4
reduction and mCPBA epoxidation,12 followed by
TPAP oxidation and the Wittig olefination, exclusively
leading to 18. The PMB group of 18 was removed with
DDQ, followed by dimethyl carbamation to afford 5. At
the final stage, exposure of the dimethyl carbamyl epox-
ide 5 to BF3ÆOEt2 at room temperature gave the desired
polyol subunit cyclic carbonate 19,13 which possessed
the same carbon framework (C1–C16) as that of 1.
The newly introduced stereochemistry at C4 and 5 of
19 was determined by the NOE experiments (Scheme 5).
3. (a) Chamberlin, J. W.; Gorman, M.; Agtarap, A. Biochem.
Biophys. Res. Commun. 1969, 34, 448–453; (b) Prouty, W.
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1053–1057.
4. Kirst, H. A.; Larsen, S. H.; Paschal, J. W.; Occolowitz, J.
L.; Creemer, L. C.; Rios Steiner, J. L.; Lobkovsky, E.;
Clardy, J. J. Antibiot. 1995, 48, 990–996.
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In conclusion, the asymmetric synthesis of the polyol
subunit 19 of 1 was accomplished in a stepwise carbon
chain construction manner. We believe that this C1–
C16 polyol subunit would be a useful synthetic interme-
diate for the total synthesis of ossamycin.
´
Rodrıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
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This work was supported by Grant-in-Aid for the 21st
Century COE program ꢀKeio Life Conjugate Chemistryꢁ,
as well as Scientific Research C from the Ministry of Edu-
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