Synthesis of (±)-dehydropentenomycin and analogues

Article abstract of DOI:10.1016/S0040-4039(02)01709-4

(±)-Dehydropentenomycin and analogues were synthesized by utilizing the intramolecular acylation of α-sulfinyl carbanions, starting from alkyl 2,2-dimethyl-1,3-dioxolanecarboxylates.

Full text of DOI:10.1016/S0040-4039(02)01709-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7385–7387
Synthesis of ( )-dehydropentenomycin and analogues†
Manat Pohmakotr,* Thiti Junpirom, Supatara Popuang, Patoomratana Tuchinda and
Vichai Reutrakul
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Received 18 July 2002; accepted 15 August 2002
Abstract—( )-Dehydropentenomycin and analogues were synthesized by utilizing the intramolecular acylation of a-sulfinyl
carbanions, starting from alkyl 2,2-dimethyl-1,3-dioxolanecarboxylates. © 2002 Elsevier Science Ltd. All rights reserved.
Dehydropentenomycin (antibiotic G-2201-C) (1a) iso-
lated from Streptomyces cattleya1 is one of the most
simple cyclopentenoid antibiotics. Other members pos-
sessing a similar skeleton, pentenomycins I–III (2) and
epipentenomycin I (3), were isolated from culture
broths of Streptomyces eurythermus2 and from car-
pophores of Perziza sp.,3 respectively. Due to their
interesting biological activities against Gram-positive
and Gram-negative bacteria, this type of compound has
received considerable attention. Although several syn-
thetic approaches to pentenomycins I–III and their
epimers both in racemic and enantiopure forms have
appeared in the literature,4a–j only few publications are
concerned with the syntheses of dehydropenteno-
mycin.4a,b In connection with our recent reports on
general approaches to highly functionalized cyclopen-
tenones as well as the preparation of ( )-pentenomycin
I (2, R1=R2=H) and its epimer4g based on the sequen-
tial intramolecular acylation of a-sulfinyl carbanions
followed by sulfoxide elimination,5 we wish to report
sulfides 5 in moderate to good yields (60–75%) as
herein a new synthetic route to ( )-dehydropenteno-
mixtures of diastereomers. These mixtures were then
mycin (1a) and its analogues (1b–d) starting from alkyl
subjected to oxidation with NaIO4 (1.1 equiv.) in
2,2-dimethyl-1,3-dioxolanecarboxylates.
aqueous methanol at 0°C to room temperature
overnight to afford the corresponding hydroxysulfox-
As summarized in Scheme 1, the key intermediates for
ides 6 as diastereomeric mixtures in 69–76% yields after
the cyclisation, hydroxysulfoxides 6 could be easily
chromatography. Cyclisation of the hydroxysulfoxides
prepared from esters 4. Treatment of enolate anions of
6 to the expected a-phenylsulfinyl cyclopentanones 7
4,6 generated by employing lithium diisopropylamide
was readily accomplished by treatment with 3.2 equiv.
(LDA, 1 equiv.) in THF at −78°C for 2 h, with 3-
of LDA in THF at −78°C for 2 h and at 0°C for a
phenylsulfanylpropanal (1.1 equiv.) provided hydroxy-
further 2 h. The formation of 7 could be envisaged to
occur through an intramolecular acylation reaction of
the initially formed a-sulfinyl carbanions derived from
Keywords: dehydropentenomycin; sulfoxides; acylation; antibiotics;
carbanions; cyclisation.
* Corresponding author. Tel.: 066-02-2015158; fax: 066-02-6445126;
6. Sulfoxide elimination of the cyclized products 7 was
effected by flash vacuum pyrolysis at 340°C (0.01–0.08
mmHg) or refluxing in dry toluene in the presence of
anhyd. CaCO3 for 10–12 h to give diastereomeric mix-
tures of 4-hydroxyspirocyclopentenones 8 in 50–87%
e-mail: scmpk@mahidol.ac.th
Dedicated to Professor Dieter Seebach on the occasion of his 65th
birthday.
†
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01709-4

7386
M. Pohmakotr et al. / Tetrahedron Letters 43 (2002) 7385–7387
Scheme 1.
Table 1. Preparation of compounds 1, 5, 6, 7, 8 and 9
Entry
R1
R2
R3
Yield (%)a
5
6
7
8
Diastereomeric ratio
9
Dehydropentenomycins 1
1
2
3
a: H
b: Me
c: H
H
Me 45–63
Quant.b
70 (55)c
76 (56)c
55 (69)c
66
87d 54:33f
73e
76h Quant.b
Me
Et
Et
Et
60
72
50d 29:21f
78
84
92
89
60e
g
77–84
62d
65e
51e
71d
51e
–
–
g
4
d: H
Pri
Me 89
Et 75
70
74
87
78
77
88
a Yield of the isolated product after preparative thin-layer chromatography (SiO2).
b Yield of the crude product.
c Yield was calculated based on compound 5.
d Flash vacuum pyrolysis of compound 7 was carried out at 340°C (0.01–0.08 mmHg).
e Obtained by refluxing in dry toluene/anhyd. CaCO3/10–12 h.
f The diastereomeric ratio of the more polar isomer:less polar isomer was determined after chromatography.
g The ratio could not be determined.
h MnO2 in CH2Cl2 was employed.
isolated yields. Oxidation of diastereomeric mixtures of
5 to the corresponding spiroenediones 9 was successfully
accomplished by employing MnO2 (2 equiv.)/CH2Cl2, rt,
overnight for 9a7 or pyridinium chlorochromate [PCC (3
equiv.)/CH2Cl2, rt, 6 h] for 9b–d. Good yields (76–84%)
of the oxidation products 9a–d were obtained. Direct
oxidation of 7a leading to the expected product 9a via
5-phenylsufinylspirocyclopenta-1,3-diones followed by
sulfoxide elimination was also investigated by using
Collin’s reagent, pyridinium chlorochromate (PCC),
pyridinium dichromate (PDC) and Swern oxidation.
However, all reactions gave unsatisfactory results; only
a trace amount of the expected product 9a could be
obtained. Hydrolysis of spiroenedione 9a with 90%
trifluoroacetic acid at 0°C for 3 h afforded ( )-dehy-
dropentenomycin (1a)8 in 88% yield after chromatogra-
phy on silica gel (EtOAc). Similarly, the analogues 1b–d9
of ( )-dehydropentenomycin (1a) could be obtained
from 9b–d in good yields under the same conditions. The
results are summarized in Table 1.
In conclusion, ( )-dehydropentenomycin (1a) and its
analogues 1b–d were synthesized starting from the
esters 4 by employing the intramolecular acylation
of a-sulfinylcarbanions followed by sulfoxide elimina-
tion as the key reactions. The procedure provides a
convenient route to this important class of com-
pounds.
Acknowledgements
V.R. would like to thank the Thailand Research Fund
for the award of a Senior Research Scholar. T.J. is
grateful to the Development and Promotion of Science
and Technology Talent Project (DSPT) for a scholarship.
Thanks are also made to the Higher Education Develop-
ment Project: Post-graduate Education Program in
Chemistry for partial support.

M. Pohmakotr et al. / Tetrahedron Letters 43 (2002) 7385–7387
7387
References
1.23–1.29 and 1.46–1.61 (each m, 2H, CHCH2CH3), 1.49
and 1.54 [each s, 6H, C(CH3)2], 4.08 (dd, J=9.23, 4.00 Hz,
1H, OCHCH2CH3), 7.27 and 7.30 (each d, J=6.49 and
6.57 Hz, 2H, CHꢀCH). 13C NMR (75 MHz, CDCl3): l
200.46, 149.15, 148.83, 112.49, 82.68, 81.44, 26.87, 25.85,
22.67, 10.90. IR (Nujol): wmax 1709, 1328, 1255, 1223, 1177,
1112, 1057, 1004, 921, 886, 841, 816, 788 cm−1. MS m/z
(%): 210 (0.19), 195 (12), 153 (25), 152 (95), 137 (9), 125
(11), 124 (35), 112 (8), 97 (12), 96 (46), 95 (20), 94 (45), 82
(63), 70 (25), 69 (50), 59 (24), 55 (16), 54 (53), 53 (16), 43
(100), 39 (38), 38 (72). Anal. calcd for C11H14O4: C, 62.84;
H, 6.71. Found: C, 63.13; H, 6.29%.
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Bull. 1974, 22, 1233–1238.
3. Bernillon, J.; Favre-Bonvin, J.; Pommier, M. T.; Arpin, N.
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burg, B. Tetrahedron Lett. 1982, 23, 5463–5466; (d)
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1984, 106, 2459–2461; (f) Achab, S.; Coson, J.-P.; Das, B.
C. J. Chem. Soc., Chem. Commun. 1984, 1040–1041; (g)
Pohmakotr, M.; Popuang, S. Tetrahedron Lett. 1991, 32,
275–278; (h) Sugahara, T.; Ogasawara, K. Synlett 1999,
419–420; (i) Seepersaud, M.; Al-Abed, Y. Tetrahedron
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5. (a) Pohmakotr, M.; Popuang, S.; Chancharunee, S. Tetra-
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Popaung, S. Tetrahedron Lett. 1990, 31, 3783–3784.
6. Ladner, W. Chem. Ber. 1983, 116, 3413–3426 and refer-
ences cited therein.
1
Compound 9d: a pale yellow solid; mp 50–51°C. H NMR
(300 MHz, CDCl3): l 0.55 and 0.96 [each d, J=6.69 and
6.52 Hz, 6H, CH(CH3)2], 1.46 and 1.49 (each s, 6H,
C(CH3)2), 1.79–187 (m, 1H, CH(CH3)2, 3.90 [d, J=9.84
Hz, 1H, OCHCH(CH3)2], 7.30 (s, 2H, CHꢀCH). 13C
NMR (75 MHz, CDCl3): l 200.71, 200.61, 149.83, 148.84,
111.74, 86.35, 78.58, 28.06, 26.76, 25.65, 20.36, 18.72. IR
(Nujol): wmax 1708, 1563, 1334, 1325, 1268, 1251, 1224,
1174, 1121, 1105, 1065, 1033, 977, 890, 850, 807, 770, 722
cm−1. MS m/z (%): 224 (M+, 0.87), 205 (4), 149 (100), 123
(2), 122 (2), 121 (3), 105 (3), 104 (6), 93 (3), 76 (6), 65 (3),
57 (3), 41 (12).
Compound 1a: viscous liquid. 1H NMR (300 MHz, ace-
tone-d6): l 3.76 (s, 2H, CH2O), 4.54–4.66 (br s, 2H, OH,
CH2OH), 7.41 (s, 2H, CHꢀCH). 13C NMR (75 MHz,
CDCl3): l 204.72, 150.48, 74.90, 64.36. IR (Neat): wmax
3444 (br), 1755, 1713 1643, 1563, 1342, 1332, 1127, 1059,
979, 913, 864 cm−1. MS m/z (%): 142 (M+, 3), 124 (85), 112
(24), 83 (29), 82 (69), 68 (24), 55 (100), 53 (23), 42 (42).
The data are in good agreement with the literature.4b
7. The oxidation of 8a using PCC to lead to 9a gave less
satisfactory results.
8. The spectral data of 1a were consistent with the reported
1
Compound 1b: mp 111–112°C. H NMR (300 MHz, ace-
values.4b
tone-d6): l 1.30 [s, 6H, C(CH3)2], 7.39 (s, 2H, CHꢀCH).
13C NMR (75 MHz, acetone-d6): l 204.54, 149.95, 79.04,
74.30, 25.16. IR (KBr): wmax 3450 (br), 1746, 1702, 1562,
1460, 1396, 1383, 1358, 1325, 1261, 1162, 1183, 1138, 1118,
1053, 988, 947, 855, 836 cm−1. MS m/z (%): 152 (M+−H2O,
24), 112 (62), 84 (15), 69 (11), 59 (100), 55 (27), 43 (49).
Compound 1c: mp 177°C (dec.). 1H NMR (300 MHz,
acetone-d6): l 0.93 (t, J=7.37 Hz, 3H, CH2CH3), 1.41–
1.56 and 1.83–2.01 (each m, 2H, CH2CH3), 2.00–3.60 (br,
2H, OH), 3.70 (dd, J=10.43, 2.11 Hz, 1H, CHCH2CH3),
7.41 and 7.44 (each d, J=6.41 and 6.41 Hz, 2H, CHꢀCH).
13C NMR (75 MHz, acetone-d6): l 205.54, 204.04, 150.52,
149.98, 77.02, 76.12, 24.33, 10.95. IR (Nujol): wmax 3420
(br), 1745, 1709, 1563, 1358, 1325, 1261, 1202, 1183, 1137,
1118, 1053, 989, 947, 855, 836, 699 cm−1. MS m/z (%): 172
(M++2, 0.70), 82 (15), 59 (36), 54 (80), 43 (100).
9. All new compounds gave spectral and analytical data
consistent with the proposed structures. Selected NMR
and physical data are listed.
1
Compound 9a: a yellow solid; mp 69–70°C. H NMR (300
MHz, CDCl3): l 1.51 [s, 6H, C(CH3)2], 4.03 (s, 2H,
CH2O), 7.30 (s, 2H, CHꢀCH). 13C NMR (75 MHz,
CDCl3): l 200.35, 148.90, 114.54, 78.51, 69.59, 25.83. IR
(Nujol): wmax 1722, 1710, 1564, 1461, 1380, 1370, 1330,
1302, 1259, 1231, 1215, 1163, 1112, 1075, 1062, 1028, 861,
834 cm−1. MS m/z (%): 182 (M+, 23), 167 (51), 164 (22),
139 (29), 124 (66), 96 (57), 82 (72), 68 (55), 59 (91), 54 (74),
43 (100), 39 (29), 31 (4). Anal. calcd for C9H10O4: C, 59.33;
H, 5.53. Found: C, 59.41; H, 5.86%.
1
Compound 9b: a pale yellow solid; mp 96–97°C. H NMR
(300 MHz, CDCl3): l 1.23, 1.57 [each s, 12H, 2×C(CH3)2],
7.27 (s, 2H, CHꢀCH). 13C NMR (75 MHz, CDCl3):
198.89, 148.84, 112.79, 87.07, 83.44, 28.80, 25.92. IR
(neat): wmax 1757, 1714, 1565, 1469, 1371, 1331, 1250, 1218,
1195, 1133, 1055, 1017, 856, 837, 744, 687 cm−1. MS m/z
(%): 210 (M+, 0.75), 166 (61), 151 (21), 149 (14), 138 (17),
123 (14), 111 (10), 94 (10), 82 (100), 69 (13), 55 (12), 43
(30). Anal. calcd for C11H14O4: C, 62.84; H, 6.71. Found:
C, 63.08; H, 6.44%.
Compound 1d: mp 182°C (dec.). 1H NMR (300 MHz,
acetone-d6): l 0.76 and 0.90 [each d, J=6.64 and 6.72 Hz,
6H, CH(CH3)2], 1.93–2.02 [m, 1H, CH(CH3)2], 3.51 [d,
J=5.23 Hz, 1H, CHCH(CH3)2], 4.73 (br t, 2H, CHO-
HCOH), 7.31 (br s, 2H, CHꢀCH). 13C NMR (75 MHz,
acetone-d6) 205.01, 203.81, 150.40, 149.76, 78.70, 78.11,
30.28, 21.60, 18.15. IR (KBr): wmax 3424 (br), 1753, 1630,
1384, 1072 cm−1. MS m/z (%) 185 (M++1, 0.10), 166 (25),
142 (8), 141 (10), 113 (24), 112 (100), 82 (24).
1
Compound 9c: a yellow solid; mp 66–67°C. H NMR (300
MHz, CDCl3): l 0.87 (t, J=7.37 Hz, 3H, CHCH2CH3),