Synthesis of (±) epipentenomycin I and III

Article abstract of DOI:10.1016/S0040-4039(02)01216-9

A synthesis of (±) epipentenomycin I and III is reported from a regioselective epoxidation of racemic 3-hydroxy- and 3-acetoxy-2-methylene-4-cyclopentenone, respectively, with dimethyldioxirane followed by hydrolytic ring-opening of the resulting epoxide.

Full text of DOI:10.1016/S0040-4039(02)01216-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6047–6049
Synthesis of ( ) epipentenomycin I and III
Weerachai Phutdhawong,a,b Stephen G. Pyne,c,* Apiwat Baramee,b Duang Buddhasukh,b
Brian W. Skeltond and Allan H. Whited
aDepartment of Chemistry, Mae Jo University, Chiang Mai 50290, Thailand
bDepartment of Chemistry, Chiang Mai University, Chiang Mai 50202, Thailand
cDepartment of Chemistry, University of Wollongong, Wollongong, NSW, 2522, Australia
dDepartment of Chemistry, University of Western Australia, Crawley, WA, 6009, Australia
Received 20 April 2002; accepted 26 June 2002
Abstract—A synthesis of ( ) epipentenomycin I and III is reported from a regioselective epoxidation of racemic 3-hydroxy- and
3-acetoxy-2-methylene-4-cyclopentenone, respectively, with dimethyldioxirane followed by hydrolytic ring-opening of the resulting
epoxide. © 2002 Elsevier Science Ltd. All rights reserved.
The pentenomycin group of natural products (com-
pounds 1–4) have antibacterial activities against both
Gram-positive and Gram-negative bacteria. Penteno-
mycin I (1) and II (2) were first isolated from Strepto-
myces eurythermus in 19731 while pentenomycin III (3)
was isolated three years later from Streptoverticillium
eurocidicum.2 Epipentenomycin I (4), however, was iso-
lated in 19893 from carpophores of Perziza sp., much
later than its first synthesis in racemic form in 1980.4,5
Their biological activities and their highly oxygenated
structures have attracted several synthetic studies on
their total synthesis,6 the synthesis of their
racemates4,5,7 and their analogues8 (e.g. epipenteno-
mycin II (5) and III (6)). We report here a diastereose-
lective synthesis of ( ) epipentenomycin I (4) and III (6)
from the diastereoselective epoxidation of 3-hydroxy-
and 3-acetoxy-2-methylene-4-cyclopentenone, respec-
tively, with dimethyldioxirane followed by hydrolytic
ring-opening of the resulting epoxide.
Treatment of freshly prepared 3-hydroxy-2-methylene-
4-cyclopentenone (7)9 with freshly distilled dimethyl-
dioxirane (DMDO) in acetone10 at rt for 12 h produced
an 83:17 mixture of the anti- and syn-epoxy-alcohols 8
and 9, respectively and the unexpected product 10. The
crude mixture was separated by flash chromatography
to give diastereomerically pure 8 and 10 in yields of 49
and 36%, respectively.11 The syn-isomer 9 could not be
isolated in pure form. The structure of 8 was clear from
spectral analysis, although its relative stereochemistry
could only be deduced from its transformation into ( )
epipentenomycin I (4). The NMR spectra of compound
10 indicated the presence of an ethyl and an acetate
group and its structure was unequivocally determined
by a single-crystal X-ray study (Fig. 1).12
While the mechanism for the formation of 10 is not
clear, this compound formally arises from the incorpo-
ration of one molecule of DMDO into 7 (Scheme 2).
O
O
OR2
OR2
OH
OH
OR1
OR1
4; epipentenomycin Ι (R1 = R2 = H)
5; epipentenomycin ΙΙ (R1 = Ac, R2 = H)
6; epipentenomycin ΙΙΙ (R1 = H, R2 =Ac)
1; pentenomycin Ι (R1 = R2 = H)
2; pentenomycin ΙΙ (R1 = Ac, R2 = H)
3; pentenomycin ΙΙΙ (R1 = H, R2 =Ac)
Keywords: epipentenomycin I and III; epoxidation; dimethyldioxirane; epoxide hydrolysis.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01216-9

6048
W. Phutdhawong et al. / Tetrahedron Letters 43 (2002) 6047–6049
Interestingly, both products 8 and 10 arise from addi-
tion of DMDO anti to the allylic hydroxyl group in 7.
Our attempts to reverse the diastereoselectivity in
favour of diastereomer 9, which should yield penteno-
mycin I after hydrolytic epoxide ring-opening, were
unsuccessful. The use of the less polar solvent CCl4 in
this reaction, conditions that should favour 9 by
enhancing H-bonding between the allylic hydroxyl
group in 7 and DMDO,13 led to poorer overall yields
due to incomplete conversion of 7 and resulted in little
changes in the diastereoselectivities.
Protic acid (H2SO4 or HClO4) or Lewis acid (BiCl3)14
catalysed hydrolysis reactions of the epoxide ring of
rac-8 to give ( ) epipentenomycin I (4) were not clean
and led to impure samples of the desired product.
However, heating a solution of rac-8 in D2O15 solution
in an NMR tube at 80°C, with monitoring by 1H NMR
spectroscopy, cleanly led to ring-opening of the epoxide
group. After freeze-drying pure ( ) epipentenomycin I
(4) was obtained in 74% yield (Scheme 1). This sample
had identical spectral characteristics to those reported
in the literature for this compound.7a
Figure 1. ORTEP plot of 10.
O
O
Me
O
O
Me
Me
O
O
+
+
O
O
OAc
In an attempt to prepare ( ) epipentenomycin II (5) we
acetylated the known alcohols rac-11a and rac-11b, to
give their respective allylic acetates, rac-12a and rac-
12b (Scheme 3). These compounds were highly crys-
talline and their relative stereochemistries were secured
by single-crystal X-ray studies.12 Treatment of the indi-
vidual isomers rac-12a and rac-12b or a mixture of
these isomers under flash vacuum pyrolysis (FVP) con-
ditions gave the novel allylic acetate rac-13 in 78%
yield.11 Treatment of rac-13 with freshly distilled
DMDO in acetone at rt for 12 h produced an 80:20
mixture of the anti- and syn-epoxy-acetates, rac-14 and
rac-15, respectively. No product corresponding to the
acetate derivative of 10 could be isolated. Purification
by flash chromatography gave an inseparable 80:20
mixture of rac-14 and rac-15 in 42% yield. Hydrolytic
ring-opening of this mixture in D2O gave, as the major
acetone,
RT, 16 h
OH
rac-9
OH
rac-8 [49%]
OH
rac-7
OH
rac-10 [36%]
[8 : 9 = 83 : 17]
D2O, 80 oC
16 h
O
OH
OH
OH
rac-4 [74%]
Scheme 1.
1
components from H NMR analysis, about a 1:1 mix-
ture of racemic epipentenomycins II and III formed
from ring-opening of rac-14 and then migration of the
secondary acetate in rac-5 to the more stable primary
Scheme 2.
Scheme 3.

W. Phutdhawong et al. / Tetrahedron Letters 43 (2002) 6047–6049
6049
position. Smith7a has demonstrated that in solution
these isomeric acetates are in equilibrium and that
chloroform solution favours the primary acetate iso-
mer. Thus this mixture was freeze-dried and purified by
PTLC using dichloromethane as eluant to give about
an 80:20 mixture of epipentenomycin III and a second
isomer, albeit in modest yield (22%). These compounds
had 1H NMR spectral data in CDCl3 that matched
closely and were similar, respectively, to that reported
for epipentenomycin III and pentenomycin III,
respectively.7a
8. (a) Verlaak, J. M. J.; Klunder, A. J. H.; Zwanenburg, B.
Tetrahedron Lett. 1982, 23, 5463; (b) Klunder, A. J. H.;
Houwen-Claassen, A. A. M.; Kooy, M. G.; Zwanenburg,
B. Tetrahedron Lett. 1987, 28, 1329; (c) Houwen-
Claassen, A. A. M.; Klunder, A. J. H.; Zwanenburg, B.
Tetrahedron 1989, 45, 7134.
9. Chantarasiri, N.; Dinprasert, P.; Thebtaranonth, C.;
Thebtaranonth, Y.; Yenjai, C. J. Chem. Soc., Chem.
Commun. 1990, 286.
10. Murray, R. W.; Singh, M. Org. Synth. 1997, 74, 91.
11. Synthesis of 8 and 9: To a solution of 7 (50 mg, 0.45
mmol) in acetone (5 ml) was added a solution of DMDO
(0.90 mmol, 0.07 M in acetone) at 0°C, and the reaction
was left to stir overnight at rt. The solvent was then
evaporated and the mixture was purified by PLC (silica
gel; 40% EtOAc/petroleum spirit) to obtain 8 (28 mg,
49%) as a viscous liquid and 10 (30 mg, 36% yield).
In conclusion we have developed a synthesis of epipen-
tenomycin I via a diastereoselective epoxidation of 7
followed by mild hydrolysis of the resulting epoxide
group. We have also found a novel oxidation product,
the compound 10, in this epoxidation reaction. We are
currently working on the synthesis of enantiomerically
pure 7 to allow the preparation of enantiomerically
pure pentenomycins and their derivatives.
1
Compound 8: H NMR (300 MHz, CDCl3): l 2.31 (br.,
OH), 3.14 (d, 1H, J=6 Hz), 3.28 (d, 1H, J=6 Hz), 4.96
(s, 1H,), 6.53 (dd, 1H, J=6, 1 Hz), 7.69 (dd, 1H, J=6, 2
Hz). 13C NMR (75 MHz, CDCl3): l 50.1 (CH2), 69.8
(CH), 137.7 (CH), 138.6 (C), 161.5 (CH), 186.0 (CO).
CIMS (70 eV) m/z 127 (M+, 100). HRCIMS (70 eV) calcd
for C6H7O3, 127.0395. Found, 127.0363 (M+).
Acknowledgements
1
Compound 9: H NMR (300 MHz, CDCl3): l 2.32 (br.,
OH), 3.34 (d, 1H, J=6 Hz), 3.41 (d, 1H, J=6 Hz), 5.12
(s, 1H,), 6.63 (d, 1H, J=6 Hz), 7.82 (d, 1H, J=6 Hz).
Compound 10: needles from DCM/petroleum spirit,
We thank The Royal Golden Jubilee Ph.D. Program
for a Ph.D. scholarship to W.P. and The University of
Wollongong for financial support.
1
mp=98–100°C, H NMR (300 MHz, CDCl3): l 0.92 (t,
3H, J=7.6 Hz), 1.71 (m, 1H, J=7.6 Hz), 2.08 (m, 1H),
2.15 (s, 3H), 3.27 (d, OH, J=4 Hz), 5.01 (br. t, 1H, J=2
Hz), 6.30 (dd, 1H, J=2, 5 Hz), 7.49 (dd, 1H, J=2, 5 Hz).
13C NMR (75 MHz, CDCl3): l 8.1 (CH3), 21.6 (CH3),
24.6 (CH2), 75.2 (CH), 89.2 (C), 132.7 (CH), 159.8 (CH),
171.9 (CO), 200.7 (CO). CIMS (70 eV) m/z 185 (M+,
100). HRCIMS (70 eV) calcd for C9H13O4, 185.0814.
Found, 185.0794 (M+).
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