A new total synthesis of pentenomycin

Article abstract of DOI:10.1016/S0040-4039(01)01099-1

A new total synthesis of enantiomerically pure pentenomycin has been achieved by the intramolecular nitrone cycloaddition of the proper γ-unsaturated aldehyde, easily accessible from L-arabinose, followed by reductive N-O bond cleavage and further oxidati

Full text of DOI:10.1016/S0040-4039(01)01099-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5769–5771
A new total synthesis of pentenomycin
John K. Gallos,* Katerina C. Damianou and Constantinos C. Dellios
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 540 06, Greece
Received 2 May 2001; revised 12 June 2001; accepted 20 June 2001
Abstract—A new total synthesis of enantiomerically pure pentenomycin has been achieved by the intramolecular nitrone
cycloaddition of the proper g-unsaturated aldehyde, easily accessible from -arabinose, followed by reductive NꢀO bond cleavage
and further oxidative deamination of the resulting aminocyclopentitol. © 2001 Elsevier Science Ltd. All rights reserved.
L
Pentenomycin antibiotics constitute a family of natural
hydroxylated cyclopentanoids, which are produced by
Streptomyces species and show moderate activity
against Gram-positive and Gram-negative bacteria.1,2
Among them, pentenomycin I 1, usually referred to
simply as pentenomycin, has attracted considerable
attention and a number of syntheses of racemic and
enantiopure material have been reported.2 We now
wish to report an efficient synthesis of enantiomerically
pure pentenomycin, starting from the naturally abun-
Swern oxidation, condensation with MeNHOH and
reflux of the resulting nitrone in chlorobenzene3 to give
in good overall yield the bicyclic oxazine 8, together
with its diastereomeric adduct in a ratio of ca. 8:1 (the
major isomer shown hereafter in Scheme 1). Since both
diastereoisomers give the same final product, they were
used further as a mixture, although they are easily
separable chromatographically.7,8
The best conditions found for the NꢀO bond cleavage
were hydrogenolysis with H2 over Pd(OH)2 in MeOH;
the aminocyclitol 9 formed was methylated with an
excess of MeI to afford the ammonium salt 10a,
expected to give the desired protected pentenomycin
11b upon oxidation of the unprotected hydroxyl group
and spontaneous elimination of the ammonium group.9
Swern oxidation, however, gave the detritylated 11b in
low yield, whereas oxidation with PDC afforded the
iodinated compound 11a in quantitative yield (98%).
Evidently, the PDC oxidises iodide to molecular iodine,
which in the presence of pyridine (from PDC) iodinates
the enone already formed.10 Repeated washing of 10a
with aqueous NaCl caused partial replacement of
iodide by chloride and further PDC oxidation gave the
desired 11b (42%) together with 11a (32%). Much more
dant L-arabinose. The crucial step of formation of the
five-membered ring involves an intramolecular nitrone
cycloaddition, a reaction we had applied some time
ago3 to the synthesis of aminocyclopentitols 4 from the
unsaturated aldehyde 2, via the adduct 3 (Fig. 1).
In order to construct the two chiral centres of penteno-
mycin with the correct absolute configuration, we
started from
to the protected
L
-arabinose, which was readily converted
L
-erythrose 5 (Scheme 1).4 The hydroxy-
methyl group was introduced by treatment of 5 with
CH2O in the presence of K2CO3 according to the
literature5 and subsequently was tritylated by standard
procedures.6 Wittig olefination of 6 with Ph3PꢁCH2
yielded the alcohol 7, which was then subjected to
Figure 1.
* Corresponding author. Fax: ++31-997679; e-mail: igallos@chem.auth.gr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01099-1

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J. K. Gallos et al. / Tetrahedron Letters 42 (2001) 5769–5771
Scheme 1. Reagents and conditions: (i) CH2O, K2CO3, MeOH, reflux, 3 days, 82%; (ii) Ph3C-Cl, pyridine (dry), 60°C, 2 days, 59%;
(iii) Ph3P+CH3Br−, 12-crown-4, n-BuLi, THF, −70“0°C, 98%; (iv) (COCl)2, DMSO, Et3N, CH2Cl2, −50 to 20°C, 30 min; (v)
MeNHOH·HCl, Na2CO3, EtOH, 20°C, 15 min; (vi) PhCl, reflux, 15 min, 53% from 7; (vii) Pd(OH)2/C, H2, MeOH, 20°C, 15 h,
52%; (viii) MeI, K2CO3, THF, 20°C or MeOTs, K2CO3, THF, reflux; (ix) PDC, CH2Cl2, 20°C, 2 h, 66% of 11b from 9 via 10b;
(x) aqueous HCl 1N, THF, 20°C, 12 h, 90%.
satisfactory results were obtained when the quaternisa-
3. Gallos, J. K.; Goga, E. G.; Koumbis, A. E. J. Chem.
Soc., Perkin Trans. 1 1994, 613–614.
tion of amine 9 was attempted with methyl p-toluene-
sulfonate.
The
resulting
trimethylammonium
4. (a) Thompson, D. K.; Hubert, C. N.; Wightman, R. H.
Tetrahedron 1993, 49, 3827–3840; (b) Hall, A.; Meldrum,
K. P.; Therond, P. R.; Wightman, R. H. Synlett 1997,
123–125; (c) Gallos, J. K.; Dellios, C. C.; Spata, E. E.
Eur. J. Org. Chem. 2001, 79–82.
5. (a) Bols, M. Carbohydrate Building Blocks; John Wiley &
Sons: New York, 1996; (b) Ho, P.-T. Tetrahedron Lett.
1978, 19, 1623–1626.
6. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed., John Wiley & Sons: New
York, 1991; (b) Kocienski, P. J. Protecting Groups;
Georg Thieme Verlag: Stuttgart, 1994.
p-toluenesulfonate 10b was smoothly oxidised with
PDC to give 11b in 66% yield from 9. Deprotection of
11b with 1N aqueous HCl in THF gave pentenomycin
1 in 90% yield, with spectroscopic and physical data
identical to those reported in the literature.2
In short, we have developed a new synthesis of enan-
tiopure pentenomycin, utilising cheap and easily avail-
able materials, applying simple and convenient
methods. The methodology used could be developed as
a new general synthesis of chiral cyclopentenones, the
scope and limitation of which is under consideration. In
addition, the aminocyclopentitols intermediates such as
9 are also of considerable importance as glycosidase
inhibitors and carbocyclic nucleoside precursors.11
7. All new compounds gave spectral and analytical data
consistent with the proposed structures. Selected NMR
and physical data are listed. Compound 7: oil, [h]D −11.9
(c 1.15, CHCl3); 1H NMR (CDCl3) l 1.33 (s, 3H), 1.49 (s,
3H), 3.18 (d, 1H, J=9.0 Hz), 3.27 (d, 1H, J=9.0 Hz),
3.65 (two dd as m, 2H), 4.12 (dd, 1H, J=7.0, 4.7 Hz),
5.24 (dd, 1H, J=10.6, 2.2 Hz), 5.45 (dd, 1H, J=17.2, 2.2
Hz), 5.93 (dd, 1H, J=17.2, 10.6 Hz), 7.25 (m, 9H), 7.35
(m, 6H); 13C NMR (CDCl3) l 26.5, 27.9, 62.4, 68.1, 81.5,
83.3, 87.3, 109.0, 116.2, 127.1, 127.9, 128.7, 135.9, 143.4;
HRMS (MALDI-FTMS) calcd (C28H30O4Na) 453.2036
(M+Na), found 453.2037, | 0.2 ppm. Compound 8: oil,
[h]D −7.5 (c 1.29, CHCl3); 1H NMR (CDCl3) l 1.07 (s,
3H), 1.44 (s, 3H), 1.98 (d, 1H, J=11.1 Hz), 2.17 (d, 1H,
J=11.1 Hz), 2.56 (s, 3H), 3.30 (s, 1H), 3.34 (d, 1H,
J=9.7 Hz), 3.41 (d, 1H, J=9.7 Hz), 3.75 (s, 1H), 4.72 (s,
1H), 7.27 (m, 9H), 7.52 (m, 6H); 13C NMR (CDCl3) l
26.4, 27.0, 28.7, 45.2, 64.3, 65.9, 77.4, 81.2, 86.5, 89.4,
111.6, 126.8, 127.6, 128.9, 144.1; HRMS (MALDI-
FTMS) calcd (C29H31NO4Na) 480.2145 (M+Na), found
480.2159, | 2.9 ppm. Compound 9: oil, [h]D −30.8 (c
References
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1
0.33, CHCl3); H NMR (CDCl3) l 1.14 (s, 3H), 1.40 (s,
3H), 1.79 (d, 1H, J=14.2 Hz), 2.20 (dt, 1H, J=14.2, 4.4
Hz), 2.30 (br s, 2H, OH, NH), 2.36 (s, 3H), 3.05 (d, 1H,

J. K. Gallos et al. / Tetrahedron Letters 42 (2001) 5769–5771
5771
J=4.4 Hz), 3.40 (d, 1H, J=9.8 Hz), 3.69 (d, 1H, J=9.8
Hz), 4.13 (s, 1H), 4.20 (d, 1H, J=4.4 Hz), 7.28 (m, 9H),
7.54 (m, 6H); 13C NMR (CDCl3) l 26.7, 27.9, 34.2, 35.1,
65.4, 66.7, 79.4, 85.8, 87.2, 94.2, 110.9, 127.0, 127.8,
fore for 9 and 10) was deduced from NOE experiments.
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128.8,
143.8;
HRMS
(MALDI-FTMS)
calcd
(C29H33NO4Na) 482.2302 (M+Na), found 482.2301, | 0.2
1
ppm. Compound 11b: oil, [h]D +15.7 (c 0.5, CHCl3); H
NMR (CDCl3) l 1.31 (s, 3H), 1.34 (s, 3H), 3.29 (d, 1H,
J 8.8 Hz), 3.48 (d, 1H, J=8.8 Hz), 5.05 (d, 1H, J=2.0
Hz), 6.28 (d, 1H, J=5.9 Hz), 7.25 (m, 15H), 7.66 (dd,
1H, J=5.9, 2.0 Hz); 13C NMR (CDCl3) l 28.4, 28.6,
62.6, 82.1, 83.8, 87.1, 115.3, 127.2, 127.9, 128.7, 134.9,
143.3, 160.1, 204.3; HRMS (MALDI-FTMS) calcd
(C28H26O4Na) 449.1723 (M+Na), found 449.1729, | 1.3
ppm.
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8. The absolute configuration of the newly formed stereo-
centres in the major isomer of cycloadduct 8 (and there-
.