Synthesis of (+)-4-desoxypentenomycin and analogues

Article abstract of DOI:10.1055/s-0029-1218690

A synthesis of (+)-4-desoxypentenomycin is reported here; it involves diastereoselective phenylsulfanylpropylation of an enolate anion derived from methyl (2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl[1,4]dioxane-2-carboxylate, obtained from D-mannitol, and is followed by sulfide oxidation, intramolecular acylation of the a-sulfinyl carbanion, sulfoxide elimination, and hydrolysis. Straightforward access to substituted analogues of (+)-4-desoxy-pentenomycin was also demonstrated by means of Suzuki-Miyaura, Sonogashira, and Heck coupling reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218690

PAPER
1453
Synthesis of (+)-4-Desoxypentenomycin and Analogues
(
+)-4-Desoxyp
u
e
ntenomycin
p
and Analog
a
ues keat Kambutong, Chutima Kuhakarn, Patoomratana Tuchinda, Manat Pohmakotr*
Department of Chemistry and Center for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University,
Rama VI Road, Bangkok 10400, Thailand
Fax +66(2)6445126; E-mail: scmpk@mahidol.ac.th
Received 26 January 2010
OMe
OMe
Abstract: A synthesis of (+)-4-desoxypentenomycin is reported
O
O
here; it involves diastereoselective phenylsulfanylpropylation of an
enolate anion derived from methyl (2R,5R,6R)-5,6-dimethoxy-5,6-
dimethyl[1,4]dioxane-2-carboxylate, obtained from D-mannitol,
and is followed by sulfide oxidation, intramolecular acylation of the
a-sulfinyl carbanion, sulfoxide elimination, and hydrolysis.
Straightforward access to substituted analogues of (+)-4-desoxy-
pentenomycin was also demonstrated by means of Suzuki–
Miyaura, Sonogashira, and Heck coupling reactions.
O
a
O
O
PhS
MeO
OMe
OMe
O
b
MeO
3
2
OMe
OMe
O
O
O
O
Key words: oxygenated cyclopentenones, desoxycyclopenten-
ones, a-sulfinyl carbanions, cyclizations, asymmetric synthesis
PhS
O
c
OMe
OMe
O
MeO
O
PhS
5
4
O
Highly oxygenated cyclopentanoids have been found in a
diverse range of natural products, for example the jas-
monates,1 prostaglandins,2 and didemnenones,3 many of
which exhibit significant biological activities. As a result,
approaches towards general and stereoselective synthesis
of this class of compounds have been extensively investi-
gated.4 Among these, the intramolecular acylation of a-
sulfinyl carbanions has proven to be a convenient entry
for the construction of functionalized cyclopentenones.5
Recently, we reported the asymmetric synthesis of pen-
tenomycins and their analogues.6 We now wish to report
the asymmetric synthesis, based on methodology de-
scribed in our earlier report, of (+)-4-desoxypentenomy-
cin (1), prepared by using the diastereoselective
phenylsulfanylpropylation of an enolate anion derived
from 2R,5R,6R-ester 2 and intramolecular acylation of a-
sulfinyl carbanion as the key steps.
d
OMe
OH
O
e
OH
O
OMe
O
O
1
6
Scheme 1 Reagents and conditions: (a) LDA, THF, –78 °C, then
PhS(CH2)3Br, HMPA, –78 °C to r.t., 66%; (b) NaIO4, MeOH, H2O,
88%; (c) LDA, THF, –78 to 0 °C, 2 h, 73%; (d) toluene, CaCO3, ref-
lux, 15 h, 80%; (e) 90% TFA, 0 °C, 5 h, 80%.
As previously demonstrated by Ley and co-workers,7 the
enolate anions of 2R,5R,6R-ester 2 and its epimer react
with electrophiles at the equatorial position in a highly
stereoselective manner (Scheme 1). This advantage was
used in the treatment of 2 with lithium diisopropylamide
in tetrahydrofuran at –78 °C for two hours, followed by
overnight alkylation with 3-bromo-1-(phenylsulfa-
nyl)propane in the presence of hexamethylphosphoramide
at –78 °C to room temperature; this afforded the expected
sulfide 3 in 66% yield as a single product. Oxidation of
sulfide 3 with sodium metaperiodate (NaIO4) in aqueous
methanol at 0 °C to room temperature provided the corre-
sponding sulfoxide 4 in 88% yield. Treatment of sulfoxide
4 with lithium diisopropylamide (2.3 equiv) in tetrahydro-
furan at –78 °C for two hours and at 0 °C for two hours
furnished a-sulfinylcyclopentanone 5 in 73% yield as a
mixture of diastereomers. The reaction proceeded via in-
tramolecular acylation of the initially formed a-sulfinyl
carbanion of sulfoxide 4. Subsequent sulfoxide elimina-
tion of 5 as a mixture of diastereomers in refluxing toluene
in the presence of calcium carbonate under an argon atmo-
sphere for 15 hours yielded the corresponding cyclopen-
tenone derivative 6 in 80% yield. Hydrolysis of the
butanediacetal protecting group of 6 was effected by the
The synthetic sequence is summarized in Scheme 1. We
started from 2R,5R,6R-ester 2, which was easily prepared
from D-mannitol as previously described by Ley.7 It was
anticipated that diastereoselective phenylsulfanylpropyla-
tion of an enolate anion derived from 2R,5R,6R-ester 2
followed by sequential oxidation, intramolecular acyla-
tion of the a-sulfinyl carbanion, sulfoxide elimination,
and hydrolysis should provide the expected desoxypen-
tenomycin 1. Furthermore, the adduct 6 was envisioned as
being a useful synthetic building block for the synthesis of
desoxypentenomycin analogues and some highly oxygen-
ated cyclopentenones.
SYNTHESIS 2010, No. 9, pp 1453–1458
x
x
.
x
x
.2
0
1
0
Advanced online publication: 09.03.2010
DOI: 10.1055/s-0029-1218690; Art ID: P01010SS
© Georg Thieme Verlag Stuttgart · New York

1454
S. Kambutong et al.
PAPER
OMe
OMe
OMe
OH
OH
O
O
O
O
O
O
b
c
d
OMe
OMe
OMe
O
e
O
O
O
I
Ph
Ph
6
7
8
11
a
OMe
OMe
OH
OH
O
O
d
O
O
Ph
OMe
OMe
O
O
O
10
9
12
Ph
Ph
d
OH
OH
Ph
O
13
Scheme 2 Reagents and conditions: (a) Pd(OAc)2, TBAB, PhI, K2CO3, DMF, 80 °C, 12 h, 72%; (b) I2, py, CCl4, 95%; (c) [PdCl2(PPh3)2],
PhB(OH)2, Na2CO3, THF, 40 °C, 10 h, 95%; (d) 90% TFA, 0 °C, 5 h; (e) [PdCl2(PPh3)2], phenylacetylene, i-Pr2NH, CuI, THF, 0 °C, 66%.
use of 90% trifluoroacetic acid at 0 °C for five hours, lead- ration of highly oxygenated cyclopentenones such as (+)-
ing to (+)-4-desoxypentenomycin (1) in 80% yield.
4-desoxypentenomycin 1, starting from readily available
2R,5R,6R-ester 2. Compound 6 was employed as a precur-
sor for the synthesis of substituted analogues of com-
pound 1 by means of Suzuki–Miyaura, Sonogashira, and
Heck coupling reactions followed by hydrolysis.
Having succeeded in synthesizing (+)-4-desoxypenteno-
mycin (1), we next demonstrated the synthetic use of the
oxygenated cyclopentenone intermediate 6 isolated dur-
ing our synthetic access to 1 in the synthesis of 4-desoxy-
pentenomycin analogues (Scheme 2). This allowed the
preparation of a-iodo derivative 7 in 95% yield by treat-
ment of compound 6 with iodine in the presence of pyri-
dine.8
1H NMR and 13C NMR spectra were recorded on Bruker DPX-300
and Bruker Avance 500 spectrometers. IR spectroscopy was carried
out on a Jasco A-302 and a Perkin-Elmer 683 infrared spectrometer.
MS was performed on a Thermo Finnigan Polaris Q mass spectrom-
eter. HRMS was carried out on either an HR-TOF-MS Micromass
model VQ-TOF2 or a Finnigan MAT 95 mass spectrometer. Mi-
croanalyses were determined with a Perkin-Elmer Elemental Ana-
lyzer 2400 CHN.
The Suzuki–Miyaura coupling reaction of 7 with phenyl-
boronic acid in tetrahydrofuran in the presence of
[PdCl2(PPh3)2] and sodium carbonate at 40 °C for 10
hours under an argon atmosphere afforded compound 8 in
95% yield (Scheme 2).9 Similarly, phenylethynyl-substi-
tuted cyclopentenone 9 was obtained in 68% yield by the
Sonogashira coupling reaction of 1 with phenylacetylene
in the presence of [PdCl2(PPh3)2], copper(I) iodide, and
diisopropylamine in tetrahydrofuran at 0 °C for one hour.10
Methyl (2S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-2-[3-(phenyl-
sulfanyl)propyl][1,4]dioxane-2-carboxylate (3)
A soln of (2R,5R,6R)-2 (1.340 g, 5.72 mmol) in THF (30 mL) was
added slowly to a THF (10 mL) soln of LDA (7.15 mmol) at –78 °C.
The mixture was stirred at –78 °C for 2 h. To this soln was added a
soln of 1-bromo-3-(phenylsulfanyl)propane (6.61 g, 28.62 mmol)
and HMPA (4 mL) in THF (15 mL). The resulting soln was stirred
at –78 °C for 2 h and quenched with sat. aq NH4Cl (30 mL). The
layers were separated and the aqueous phase was extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed
with H2O (20 mL) and brine (20 mL) and dried (Na2SO4). The or-
ganic phase was concentrated to give a crude pale yellow liquid.
Column chromatography (silica gel, EtOAc–hexanes, 13:87) gave
the title compound.
Our success with the Suzuki–Miyaura and Sonogashira
coupling reactions encouraged us to carry out the Heck
coupling reaction.11 The reaction of 6 with iodobenzene in
the presence of palladium(II) acetate, tetrabutylammoni-
um bromide, and potassium carbonate in N,N-dimethyl-
formamide at 60 °C under an argon atmosphere for 12
hours provided the expected b-phenylcyclopentenone 10
in 72% yield (Scheme 2). Standard acid-catalyzed hydrol-
ysis of the butanediacetal protecting group (90% TFA,
0 °C, 5 h) of compounds 8, 9, and 10 gave the correspond-
ing 4-desoxypentenomycin analogues 11, 12, and 13 in
82, 74, and 95% yield, respectively.
Yield: 1.451 g (66%); pale yellow liquid; single diastereomer;
[a]D29 –167.7 (c 0.7, CHCl3).
IR (neat): 1715 (s), 1585 (m), 1481 (m), 1298 (s), 1196 (s), 987 (s),
747 (s), 692 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28–7.02 (m, 5 H, ArH), 4.03 (d,
J = 11.5 Hz, 1 H, OCHH), 3.61 (s, 3 H, CO2CH3), 3.5 (d, J = 11.5
Hz, 1 H, OCHH), 3.18 (s, 3 H, OCH3), 3.14 (s, 3 H, OCH3), 2.90–
In conclusion, the synthetic utility of the intramolecular
acylation of a-sulfinyl carbanions was demonstrated to be
an efficient and general synthetic approach for the prepa-
Synthesis 2010, No. 9, 1453–1458 © Thieme Stuttgart · New York

PAPER
(+)-4-Desoxypentenomycin and Analogues
1455
2.85 (m, 2 H, SCH2), 1.82–1.72 (m, 2 H, CCH2), 1.63–1.44 (m, 2 H,
CH2CH2), 1.22 (s, 3 H, CH3), 1.19 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 173.2 (C=O), 136.0 (C), 129.3
(2 × CH), 128.8 (2 × CH), 125.9 (CH), 99.5 (C), 98.0 (C), 73.4 (C),
61.8 (CH2), 51.9 (CH3), 50.3 (CH3), 48.0 (CH3), 36.3 (CH2), 33.7
(CH2), 22.4 (CH2), 17.75 (CH3), 17.71 (CH3).
1H NMR (300 MHz, CDCl3): d = 7.70–7.61 (m, 2 × 2 H, ArH),
7.59–7.48 (m, 2 × 3 H, ArH), 4.33 (br d, J = 9.5 Hz, 1 H), 3.81 (d,
J = 11.9 Hz, 2 H), 3.74 (d, J = 11.9 Hz, 1 H), 3.59 (br d, J = 9.5 Hz,
1 H), 3.38 (d, J = 12.0 Hz, 1 H), 3.28 (s, 3 H, OCH3), 3.19 (s, 3 H,
OCH3), 3.17 (s, 3 H, OCH3), 3.16 (s, 3 H, OCH3), 2.50–2.25 (m, 1
H), 2.00–1.92 (m, 1 H), 1.85–1.50 (m, 3 H), 1.28 (s, 3 H, CH3), 1.27
(s, 3 H, CH3), 1.26 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 0.21 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 206.2 (C=O), 206.1 (C=O), 142.4
(C), 139.5 (C), 131.8 (CH), 131.0 (CH), 129.2 (2 × CH), 128.9
(2 × CH), 125.4 (2 × CH), 124.1 (2 × CH), 99.5 (C), 99.4 (C), 98.2
(2 × C), 76.3 (C), 75.9 (C), 68.0 (CH), 68.8 (CH), 58.6 (CH2), 58.3
(CH2), 49.1 (CH3), 48.9 (CH3), 48.2 (CH3), 48.1 (CH3), 32.4 (CH2),
32.0 (CH2), 18.4 (CH3), 18.3 (CH3), 17.8 (CH3), 17.7 (CH3), 16.0
(CH2), 14.8 (CH2).
MS (EI): m/z (%) = 384 (16), 353 (100), 149 (25), 127 (19).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H28O6SNa:
407.1503; found: 407.1483.
Methyl (2S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-2-[3-(phenyl-
sulfinyl)propyl][1,4]dioxane-2-carboxylate (4)
Powdered NaIO4 (0.35 g, 3.3 mmol) and H2O (5 mL) were mixed in
a round-bottomed flask and the mixture was brought to 0 °C by
cooling in an ice bath. To this mixture was added dropwise a soln of
(2S,5R,6R)-3 (1.153 g, 3.00 mmol) in MeOH (12 mL). The resulting
mixture was stirred at 0 °C to r.t. overnight. The precipitate of
NaIO3 was filtered and washed several times with EtOAc. The or-
ganic layer was separated and the aqueous layer was extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed
with H2O (20 mL) and brine (20 mL), and dried (Na2SO4). Filtration
followed by evaporation gave a crude product as yellow liquid. Col-
umn chromatography (silica gel, EtOAc–hexanes, 80:20) gave the
title compound.
MS (EI): m/z (%) = 368 [M+] (1), 202 (43), 173 (50), 149 (91), 115
(99), 97 (100), 73 (99).
HRMS (ESI-TOF): m/z [M]+ calcd for C18H23O6S: 367.1215; found:
367.1219.
(5S,7R,8R)-7,8-Dimethoxy-7,8-dimethyl-6,9-dioxa-
spiro[4.5]dec-2-en-1-one (6)
A mixture of (5S,7R,8R)-5 (0.541 g, 1.47 mmol) and anhyd CaCO3
(0.25 g, 2.5 mmol) in anhyd toluene (20 mL) was refluxed at 110 °C
for 15 h under an argon atmosphere. Filtration followed by evapo-
ration gave a residue, which was purified by preparatory TLC (silica
gel, EtOAc–hexanes, 20:80).
Yield: 1.056 g (88%); pale yellow liquid; a mixture of two diaste-
reomers.
Yield: 0.2845 g (80%); colorless liquid; a single diastereomer;
IR (neat): 1732 (s), 1444 (s), 1246 (s), 1148 (s), 1093 (s) cm–1.
[a]D29 –78.37 (c 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.60–7.45 (m, 2 × 5 H, ArH), 4.03
(d, J = 11.5 Hz, 1 H, OCHH), 4.02 (d, J = 11.5 Hz, 1 H, OCHH),
3.68 (s, 3 H, CO2CH3), 3.63 (s, 3 H, CO2CH3), 3.56 (d, J = 11.5 Hz,
1 H, OCHH), 3.51 (d, J = 11.5 Hz, 1 H, OCHH), 3.17 (s, 3 H,
OCH3), 3.15 (s, 3 H, OCH3), 3.12 (s, 3 H, OCH3), 3.12 (s, 3 H,
OCH3), 2.74–2.69 (m, 2 × 2 H, SOCH2), 1.85–1.66 (m, 2 × 4 H,
CH2CH2), 1.21 (s, 3 H, CH3), 1.19 (s, 2 × 3 H, CH3), 1.18 (s, 3 H,
CH3).
IR (Nujol): 1722 (s), 1588 (m), 1456 (s), 1114 (s), 1076 (m), 1058
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57 (dt, J = 6.0, 2.9 Hz, 1
H, =CHb), 6.08 (dt, J = 6.0, 2.1 Hz, 1 H, =CHa), 4.12 (d, J = 10.8
Hz, 1 H, OCHH), 3.38 (s, 3 H, OCH3), 3.37 (d, J = 10.8 Hz, 1 H,
CHH), 3.25 (s, 3 H, OCH3), 2.84 (m, 2 H, CCH2), 1.30 (s, 3 H, CH3),
1.25 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 172.98 (C=O), 172.90 (C=O),
143.59 (C), 143.52 (C), 130.9 (2 × CH), 129.1 (4 × CH), 123.9
(4 × CH), 99.5 (C), 99.47 (C), 98.0 (C), 97.9 (C), 73.25 (C), 73.21
(C), 61.5 (CH2), 61.4 (CH2), 57.0 (CH2), 56.9 (CH2), 52.0 (CH3),
51.9 (CH3), 50.3 (2 × CH3), 48.01 (CH3), 48.02 (CH3), 35.9 (CH2),
35.8 (CH2), 17.65 (2 × CH3), 17.62 (2 × CH3), 16.3 (CH2), 16.2
(CH2).
13C NMR (75 MHz, CDCl3): d = 205.5 (C=O), 162.5 (CH), 131.6
(CH), 100.6 (C), 99.4 (C), 76.7 (C), 64.8 (CH2), 48.2 (CH2), 47.8
(CH2), 43.5 (CH2), 18.9 (CH3), 18.7 (CH3).
MS (EI): m/z (%) = 243 [M+ + 1] (1), 211 (100), 179 (17), 94 (20),
73 (31).
HRMS (ESI): m/z [M + Na]+ calcd for C12H18O5Na: 265.1052;
found: 265.1054.
MS (EI): m/z (%) = 400 [M+] (7), 368 (25), 336 (100), 251 (17), 127
(26), 115 (25), 67 (37).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H28O7SNa:
423.1452; found: 423.1424.
(+)-4-Desoxypentenomycin (1)
(5S,7R,8R)-6 (0.114 g, 0.43 mmol) was treated with 90% TFA (5
mL) at 0 °C. The mixture was slowly warmed to r.t. and was further
stirred for an additional 5 h. The mixture was freeze-dried overnight
to give a crude product, which was purified by preparatory TLC (sil-
ica gel, MeOH–EtOAc, 5:95).
(5S,7R,8R)-7,8-Dimethoxy-7,8-dimethyl-2-(phenylsulfinyl)-6,9-
dioxaspiro[4.5]decan-1-one (5)
A soln of (2S,5R,6R)-4 (1.07 g, 2.67 mmol) in THF (5 mL) was add-
ed slowly to a THF (8 mL) soln of LDA (6.14 mmol), prepared by
reaction of N,N-diisopropylamine (0.86 mL, 6.14 mmol) with 1.35
M n-BuLi in hexane (4.6 mL, 6.2 mmol)] at –78 °C. The reaction
mixture was stirred at –78 °C for 2 h and at 0 °C for 2 h before it
was quenched with sat. aq NH4Cl (30 mL). The aqueous phase was
extracted with EtOAc (3 × 30 mL). The combined organic phase
was washed with H2O (30 mL) and brine (20 mL), and then dried
(Na2SO4) to provide a crude product. Column chromatography (sil-
ica gel, EtOAc–hexanes, 20:80 to 35:65) gave the title compound.
Yield: 48 mg (80%); colorless viscous liquid; [a]D29 +214.54 (c 0.2,
CHCl3).
IR (neat): 3420 (s), 3242 (s), 1704 (s), 1633 (m), 1583 (m), 1052 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (dt, J = 5.9, 2.9 Hz, 1
H, =CHb), 6.15–6.12 (m, 1 H, =CHa), 3.56 (s, 2 H, CH2OH), 2.70
(br s, 2 H, CCH2), 2.1 (br s, 2 H, OH).
13C NMR (75 MHz, CDCl3): d = 210.1 (C=O), 163.0 (CH), 131.1
(CH), 76.0 (C), 66.9 (CH2), 39.7 (CH2).
MS (EI): m/z (%) = 128 [M+] (27), 115 (38), 97 (64), 81 (73), 67
(93), 57 (100).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C6H8O3Na: 151.0371;
Yield: 0.715 g (73%); pale yellow viscous liquid; a mixture of dia-
stereomers.
IR (neat): 1745 (m), 1456 (m), 1446 (m), 1142 (m), 1043 (m) cm–1.
found: 151.0366.
Synthesis 2010, No. 9, 1453–1458 © Thieme Stuttgart · New York

1456
S. Kambutong et al.
PAPER
(5S,7R,8R)-2-Iodo-7,8-dimethoxy-7,8-dimethyl-6,9-dioxa-
spiro[4.5]dec-2-en-1-one (7)
mmol) in THF (1 mL) was treated with N,N-diisopropylamine (0.49
mL, 3.5 mmol) at 0 °C. The resulting yellow to dark brown soln was
stirred at 0 °C for 1 h. The mixture was partitioned between Et2O
(10 mL) and 1 M aq HCl (10 mL) and extracted with Et2O (3 × 20
mL). The combined organic layers were washed with brine (2 × 10
mL) and dried (Na2SO4). Filtration followed by concentration gave
a crude reaction mixture, which was purified by column chromatog-
raphy (silica gel, EtOAc–hexanes, 18:82).
A soln of (5S,7R,8R)-6 (0.741 g, 3.06 mmol) in pyridine (14 mL)
and CCl4 (7 mL) was treated with a soln of I2 (3.084 g, 12.23 mmol)
in CCl4 (7 mL). After stirring for 1 h at r.t. in the dark, the mixture
was diluted with Et2O (70 mL) and washed successively with H2O
(3 × 15 mL), 1 M aq HCl (5 mL), sat. aq Na2S2O3 (20 mL), and
brine (15 mL). The organic layer was dried (Na2SO4). Filtration fol-
lowed by evaporation gave a residue, which was purified by column
chromatography (silica gel, EtOAc–hexanes, 17:83).
Yield: 145.7 mg (66%); pale yellow viscous liquid; [a]D29 –24.5 (c
0.34, CHCl3).
Yield: 1.07 g (95%); pale yellow viscous oil which was unstable
IR (neat): 2992 (s), 2834 (s), 1731 (s), 1574 (s), 1463 (m), 1372 (s),
1110 (s), 972 (m) cm–1.
upon standing at r.t.; [a]D29 –75.13 (c 0.25, CHCl3).
IR (Nujol): 1715 (s), 1574 (s), 1462 (m), 1008 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (t, J = 3.1 Hz, 1 H, =CH),
7.44–7.38 (m, 2 H, ArH), 7.28–7.22 (m, 3 H, ArH), 4.18 (d, J = 9.3
Hz, 1 H, OCHH), 3.42 (s, 3 H, OCH3), 3.40 (d, J = 9.3 Hz, 1 H,
OCHH), 3.27 (s, 3 H, OCH3), 2.92 (dd, J = 15.0, 3.0 Hz, 2 H, CH2),
1.31 (s, 3 H, CH3), 1.27 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 201.6 (C=O), 162.4 (CH), 131.8
(2 × CH), 128.8 (CH), 128.3 (2 × CH), 127.3 (C), 122.2 (C), 100.9
(C), 99.6 (C), 95.7 (C), 79.6 (C), 77.2 (C), 64.9 (CH2), 48.3 (CH3),
47.9 (CH3), 42.3 (CH2), 18.9 (CH3), 18.7 (CH3).
1H NMR (300 MHz, CDCl3): d = 7.96 (app t, J = 2.9 Hz, 1
H, =CH), 4.21 (d, J = 10.8 Hz, 1 H, OCHH), 3.44 (d, J = 10.8 Hz, 1
H, OCHH), 3.42 (s, 3 H, OCH3), 3.30 (s, 3 H, OCH3), 2.99 (dd,
J = 19.5, 2.8 Hz, 1 H, CHCHHA), 2.89 (dd, J = 19.5, 2.8 Hz, 1 H,
CHCHHB), 1.35 (s, 3 H, CH3), 1.29 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 200.2 (C=O), 167.6 (CH), 100.9
(C), 99.5 (C), 99.3 (C), 74.2 (C), 64.6 (CH2), 48.3 (CH2), 47.9
(CH2), 45.9 (CH2), 18.8 (CH3), 18.6 (CH3).
MS (EI): m/z (%) = 368 [M+] (0.13), 337 (26), 220 (100), 101 (40),
MS (EI): m/z (%) = 241 [M+ – phenylacetylene] (1), 166 (20), 165
93 (40), 73 (68).
(100), 153 (28), 139 (34), 115 (39).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H17IO5Na:
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H22O5Na: 365.1364;
391.0017; found: 391.0015.
found: 365.1356.
(5S,7R,8R)-7,8-Dimethoxy-7,8-dimethyl-2-phenyl-6,9-dioxa-
spiro[4.5]dec-2-en-1-one (8)
(5S,7R,8R)-7,8-Dimethoxy-7,8-dimethyl-3-phenyl-6,9-dioxa-
spiro[4.5]dec-2-en-1-one (10)
Under an argon atmosphere, a round-bottomed flask was charged
with phenylboronic acid (49 mg, 0.406 mmol), (5S,7R,8R)-7 (100
mg, 0.271 mmol), and [PdCl2(PPh3)2] (11 mg, 5 mol%). THF (2
mL) was added followed by 2 M aq Na2CO3 (0.7 mL, 1.4 mmol).
The resulting mixture was heated overnight at 40 °C under an argon
atmosphere. The mixture was cooled to r.t. and EtOAc (10 mL) was
added followed by sat. aq NaHCO3 (20 mL) and H2O (15 mL). The
aqueous layer was extracted with EtOAc (2 × 10 mL). The com-
bined organic layers were washed with 0.5 N NaOH (2 × 10 mL)
and brine (2 × 10 mL) and dried (Na2SO4). Filtration followed by
evaporation gave a crude product, which was purified by column
chromatography (silica gel, EtOAc–hexanes, 20:80).
DMF (5 mL) was added to a mixture of (5S,7R,8R)-6 (106 mg,
0.438 mmol), PhI (0.96 mL, 0.48 mmol), Pd(OAc)2 (26.6 mg, 0.116
mmol), K2CO3 (181.5 mg, 2.409 mmol), and TBAB (253.8 mg, 0.88
mmol), and the resulting mixture was heated at 80 °C under an ar-
gon atmosphere for 12 h. After cooling to r.t., the mixture was dilut-
ed with H2O (20 mL) and extracted with EtOAc (3 × 25 mL). The
combined organic extracts were washed with H2O (15 mL) and
brine (15 mL) and dried (Na2SO4). Filtration followed by evapora-
tion gave a crude product, which was purified by preparatory TLC
(silica gel, EtOAc–hexanes, 20:80).
Yield: 99.8 mg (72%); pale yellow viscous liquid; [a]D29 –43.04 (c
0.1, CHCl3).
Yield: 82 mg (95%); white solid; mp 148–150 °C; [a]D29 –58.28 (c
0.2, CHCl3).
IR (Nujol): 1704 (s), 1607 (m), 1462 (s), 1118 (s), 1052 (m) cm–1.
IR (neat): 3061 (m), 1710 (s), 1597 (s), 1571 (s), 1494 (s), 1037 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.60–7.52 (m, 2 H, ArH), 7.42–
7.30 (m, 3 H, ArH), 6.40 (s, 1 H, =CH), 4.21 (d, J = 10.9 Hz, 1 H,
OCHH), 3.46 (d, J = 10.9 Hz, 1 H, OCHH), 3.43 (s, 3 H, OCH3),
3.35 (s, 3 H, OCH3), 3.18 (br, 2 H, CCH2), 1.36 (s, 3 H, CH3), 1.28
(s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 204.5 (C=O), 170.9 (C), 133.6 (C),
131.6 (CH), 128.9 (2 × CH), 126.9 (2 × CH), 124.3 (CH), 100.7
(C), 99.5 (C), 78.2 (C), 65.0 (CH2), 48.3 (CH3), 47.9 (CH3), 43.4
(CH2), 19.0 (CH3), 18.7 (CH3).
MS (EI): m/z (%) = 319 [M+ + 1] (6), 265 (55), 251 (100), 215 (33),
239 (36).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H22O5Na: 341.1364;
found: 341.1352.
1H NMR (300 MHz, CDCl3): d = 7.67 (app t, J = 2.9 Hz, 1
H, =CH), 7.62 (d, J = 6.5 Hz, 2 H, ArH), 7.30–7.21 (m, 3 H, ArH),
4.19 (d, J = 10.7 Hz, 1 H, OCHH), 3.43 (d, J = 10.7 Hz, 1 H,
OCHH), 3.42 (s, 3 H, OCH3), 3.28 (s, 3 H, OCH3), 2.91 (dd, J = 9.5,
3.1 Hz, 1 H, CHCHHA), 2.84 (dd, J = 9.5, 3.1 Hz, 1H, CHCHHB),
1.32 (s, 3 H, CH3), 1.28 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 203.4 (C=O), 156.1 (CH), 140.4
(C), 131.1 (C), 128.5 (CH), 128.3 (2 × CH), 126.7 (2 × CH), 100.8
(C), 99.5 (C), 78.5 (C), 65.2 (CH2), 48.3 (CH3), 47.8 (CH3), 41.4
(CH2), 19.0 (CH3), 18.7 (CH3).
MS (EI): m/z (%) = 319 [M+ + 1] (0.05), 142 (76), 141 (100), 115
(77).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H22O5Na: 341.1364;
found: 341.1347.
(+)-5-Hydroxy-5-(hydroxymethyl)-2-phenylcyclopent-2-enone
(11)
(5S,7R,8R)-7,8-Dimethoxy-7,8-dimethyl-2-(phenylethynyl)-6,9-
dioxaspiro[4.5]dec-2-en-1-one (9)
Under an argon atmosphere, a mixture of (5S,7R,8R)-7 (238 mg,
0.646 mmol), phenylacetylene (0.328 mL, 3.232 mmol),
[PdCl2(PPh3)2] (23 mg, 0.032 mmol), and CuI (12.8 mg, 0.064
Compound (5S,7R,8R)-8 (71 mg, 0.223 mmol) was treated with
90% TFA (2 mL) at 0 °C. The mixture was slowly warmed to r.t.
and further stirred for an additional 5 h. The mixture was freeze-
dried overnight to give a crude product, which was purified by pre-
paratory TLC (silica gel, EtOAc–hexanes, 1:1).
Synthesis 2010, No. 9, 1453–1458 © Thieme Stuttgart · New York

PAPER
(+)-4-Desoxypentenomycin and Analogues
1457
Yield: 37.4 mg (82%); white solid; mp 130–134 °C; [a]D29 +48.28
(c 2.0, EtOH).
Acknowledgment
We thank the Thailand Research Fund (BRG4980005 to MP), the
Center for Innovation in Chemistry (PERCH-CIC), and the Com-
mission on Higher Education (CHE-RES-RG) for financial support.
IR (Nujol): 3401 (m), 2924 (s), 1693 (s), 1571 (m), 1089 (m), 1051
(s), 998 (m) cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.88 (t, J = 2.9 Hz, 1 H, =CH),
7.64 (d, J = 7.4 Hz, 2 H, ArH), 7.22–7.12 (m, 3 H, ArH), 4.40 (s, 1
H, OH), 3.95 (t, J = 5.6 Hz, 1 H, CH2OH), 3.59 (dd, J = 10.5, 5.1
Hz, 1 H, CHCHH), 3.46 (dd, J = 10.5, 5.1 Hz, 1 H, CHCHH), 2.91
(dd, J = 19.2, 2.8 Hz, 1 H, CHHOH), 2.46 (dd, J = 19.2, 2.8 Hz, 1
H, CHHOH).
13C NMR (75 MHz, CDCl3): d = 208.0 (C=O), 158.0 (CH), 141.0
(C), 132.8 (C), 129.05 (2 × CH), 129.01 (CH), 127.5 (2 × CH), 78.6
(C), 66.9 (CH2), 31.2 (CH2).
References
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MS (EI): m/z (%) = 205 [M+ + 1] (1), 128 (31), 115 (100), 89 (24).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H12O3Na: 227.0683;
found: 227.0678.
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2-enone (12)
Compound (5S,7R,8R)-9 (107 mg, 0.313 mmol) was treated with
90% TFA (1 mL) at 0 °C. The mixture was slowly warmed to r.t.
and further stirred for an additional 5 h. The mixture was freeze-
dried overnight to give a crude product, which was purified by pre-
paratory TLC (silica gel, EtOAc–hexanes, 7:3).
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Yield: 52.9 mg (74%); colorless viscous liquid; [a]D29 +25.23 (c 0.5,
EtOH).
IR (neat): 3417 (s), 2229 (m), 1713 (s), 1571 (m), 1140 (m), 1051
(m) cm–1.
1H NMR (300 MHz, acetone-d6 + D2O): d = 7.94 (t, J = 3.0 Hz, 1
H, =CH), 7.48–7.32 (m, 5 H, ArH), 3.63 (d, J = 10.6 Hz, 1 H,
CHHOH), 3.50 (d, J = 10.6 Hz, 1 H, CHHOH), 3.08 (dd, J = 20.2,
3.2 Hz, 1 H, CHCHH), 2.63 (dd, J = 20.2, 3.2 Hz, 1 H, CHCHH).
13C NMR (75 MHz, CDCl3): d = 206.6 (C=O), 165.7 (CH), 132.1
(2 × CH), 129.6 (CH), 129.3 (CH), 127.5 (2 × C), 122.9 (C), 95.0
(C), 81.0 (C), 77.2 (C), 65.8 (CH2), 40.1 (CH2).
MS (EI): m/z (%) = 252 [M+ + 1] (2), 141 (74), 115 (100).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H12O3Na: 251.0683;
found: 251.0666.
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(13)
Compound (5S,7R,8R)-10 (111 mg, 0.348 mmol) was treated with
90% TFA (9 mL) at 0 °C. The mixture was slowly warmed to r.t.
and further stirred for an additional 5 h. The mixture was freeze-
dried overnight to give a crude product, which was purified by pre-
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(h) Phutdhawong, W.; Pyne, S. G.; Baramee, A.;
Yield: 67.6 mg (95%); white solid; mp 112–115 °C; [a]D29 +219.8
(c 0.2, EtOH).
IR (Nujol): 3315 (s), 1695 (s), 1463 (m), 1057 (m), 1039 (m), 727
(m), 698 (m) cm–1.
1H NMR (300 MHz, acetone-d6 + D2O): d = 7.81 (m, 2 H, ArH),
7.56–7.48 (m, 3 H, ArH), 6.64 (s, 1 H, =CH), 3.75 (d, J = 11.0 Hz,
1 H, CHHOH), 3.62 (d, J = 11.0 Hz, 1 H, CHHOH), 3.48 (d,
J = 18.0 Hz, 1 H, CHH), 3.04 (d, J = 18.0 Hz, 1 H, CHH).
13C NMR (75 MHz, CDCl3): d = 211.4 (C=O), 175.1 (C), 134.7 (C),
133.1 (CH), 130.1 (2 × CH), 128.4 (2 × CH), 125.2 (CH), 79.0 (C),
66.4 (CH2), 41.4 (CH2).
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found: 227.0670.
Synthesis 2010, No. 9, 1453–1458 © Thieme Stuttgart · New York

1458
S. Kambutong et al.
PAPER
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Synthesis 2010, No. 9, 1453–1458 © Thieme Stuttgart · New York