Asymmetric synthesis of pentenomycin I, epipentenomycin I, and their analogs

Article abstract of DOI:10.1016/j.tet.2008.04.089

The synthetic utility of the intramolecular acylation of α-sulfinyl carbanions as an efficient and general synthetic approach for the preparation of (-)-pentenomycin I (1) and (-)-epipentenomycin I (5) and their enantiomers (ent-1 and ent-5), starting fro

Full text of DOI:10.1016/j.tet.2008.04.089

Tetrahedron 64 (2008) 6315–6323
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of pentenomycin I, epipentenomycin I, and their analogs
*
Manat Pohmakotr , Supakeat Kambutong, Patoomratana Tuchinda, Chutima Kuhakarn
Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthetic utility of the intramolecular acylation of a-sulfinyl carbanions as an efficient and general
Received 5 February 2008
Received in revised form 11 April 2008
Accepted 24 April 2008
synthetic approach for the preparation of (ꢀ)-pentenomycin I (1) and (ꢀ)-epipentenomycin I (5) and
their enantiomers (ent-1 and ent-5), starting from chiral (2S,5S,6S)-ester 6 and ent-6, respectively, has
been demonstrated. Easy accesses to pentenomycin analogs have also been demonstrated through the
Pummerer, Suzuki–Miyaura, and Sonogashira reactions.
Available online 29 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor Dieter Seebach on
the occasion of his 70th birthday
1. Introduction
starting from (ꢁ)-methyl glycerate acetonide.13 We report herein
asymmetric synthesis of pentenomycin I and epipentenomycin I
Natural products containing highly oxygenated cyclopentenoid
skeleton, for example, cryptosporiopsin,1 kjellmanianone,2 reduc-
tiomycin,3 and didemnenones,4 have attracted considerable at-
tention due to their interesting biological activities. Among these
classes of compounds, pentenomycins I–III (1–3) and dehy-
dropentenomycin (4) are representatives of small highly oxygen-
ated cyclopentenone antibiotics (Fig. 1). Pentenomycin I (1) and
pentenomycin II (2) were first isolated from aerobic culture broths
of a mutant strain of Streptomyces eurythermus.5 Pentenomycin III
(3)6a and dehydropentenomycin (4)6b (antibiotic G-2201-C) were
isolated from Streptoverticillium eurocidicum SF-1768 and Strepto-
myces cattleya, respectively. (þ)-Epipentenomycin I (ent-5) was
found in carpophores of Perziza sp. collected from horse manure.7
Pentenomycins I and II (1 and 2) exhibit moderate to strong activity
in vitro against a variety of both Gram-positive and Gram-negative
bacteria.5 Because of their important biological activities as well as
their highly oxygenated structures, there have been several studies
directed toward the synthesis of pentenomycins and analogs in
both enantiomeric and racemic forms.8,9
and their analogs starting from an appropriate chiral ester 6 or ent-
6.14 A retrosynthetic analysis of (ꢀ)-pentenomycin I (1) and
(ꢀ)-epipentenomycin I (5) and their enantiomers is presented in
Figure 2. Of interest to our laboratory is the convergent synthesis of
highly functionalized cyclopentenones via intramolecular acylation
of a
-sulfinyl carbanions.10,13 Accordingly, we anticipated that the
key feature of our retrosynthetic analysis is a diastereoselective
hydroxyalkylation of the enolate anion derived from chiral ester 6
with 3-phenylsulfanylpropanal, which, after oxidation, leads to the
expected equatorial-sulfoxide 8. The sulfinylcyclopentanone 9
would be constructed via the intramolecular acylation of a-sulfinyl
carbanion generated from sulfinylester 8. Finally, pyrolysis followed
by hydrolysis should provide the required pentenomycin I (1) and
epipentenomycin I (5) with high enantioselectivity. In the forward
synthetic sense, (ꢀ)-pentenomycin I (1) and (ꢀ)-epipentenomycin I
(5) are derived from chiral ester 6 while ent-6 provides (þ)-pen-
tenomycin I (ent-1) and (þ)-epipentenomycin I (ent-5).
Efforts toward the synthesis of (ꢀ)-pentenomycin I (1) and
(ꢀ)-epipentenomycin I (5) began with the chiral ester 6 (Scheme 1).
O
2. Results and discussion
Pentenomycin I (1) R1 = R2 = H
OR1
Pentenomycin II (2) R1 = H, R2 = Ac
Pentenomycin III (3) R1 = Ac, R2 = H
OH
Previously, we reported intramolecular acylation of
carbanions as general strategies for the preparation of highly
functionalized cyclopentenones,10 cyclohexenones,11 and
-un-
saturated- - and
-butyrolactones.12 The method was successfully
a-sulfinyl
OR2
a,b
O
O
g
d
OR1
OH
OH
OH
applied to the racemic synthesis of (ꢁ)-pentenomycin I (1) and
(ꢁ)-epipentenomycin I (5) as well as dehydropentenomycin I (4),
O
OH
Epipentenomycin I (5)
Dehydropentenomycin (4)
* Corresponding author. Tel.: þ66 2 201 5158; fax: þ66 2 354 7151.
E-mail address: scmpk@mahidol.ac.th (M. Pohmakotr).
Figure 1. Pentenomycins, dehydropentenomycin, and epipentenomycin I.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.089

6316
M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
OH
OH
HO
HO
HO
HO
OMe
OH
O
O
O
O
(-)-Pentenomycin I (1)
(-)-Epipentenomycin I (5)
OMe
SPh
HO
OH
HO
O
9
OH
O
OH
O
OH
OMe
OH
O
(+)-Epipentenomycin I (ent-5)
O
O
(+)-Pentenomycin I (ent-1)
SPh
OMe
OMe
O
O
8
OMe
OMe
O
O
O
O
O
O
MeO
OMe
H
OMe
ent-6
OMe H
(2S,5S,6S)-6
Figure 2. Retrosynthetic analysis.
Ley and co-workers previously reported that the enolate anions of
(2S,5S,6S)-ester 6 and ent-6 reacted with electrophiles at the
equatorial position with high stereoselectivity.14,15 Thus, treatment
protecting group of 10A and 10B using 90% TFA at 0 ꢂC for 5 h
readily afforded (ꢀ)-pentenomycin I (1) and (ꢀ)-epipentenomycin I
(5) in quantitative yield. Chemical structures and optical proper-
ties of the synthesized (ꢀ)-pentenomycin I (1) and (ꢀ)-epi-
pentenomycin I (5) were established and confirmed by comparing
the 1H NMR and 13C NMR as well as the sign of the optical rotations
with those reported in the literature. The data are in good agree-
ment with the reported values.5,9
of (2S,5S,6S)-ester
6 with lithium diisopropylamide (LDA)
(1.25 equiv) followed by reaction with 3-phenylsulfanylpropanal
afforded the expected sulfide 7 in 66% yield as a mixture of di-
astereomers. Separation of the diastereomers was made by column
chromatography to give 7A and 7B in 34 and 32% yields, re-
spectively. It is worth mentioning that axial adducts were not ob-
served as revealed by 1H NMR, 13C NMR as well as TLC analysis.
Oxidation of sulfides 7A and 7B with sodium metaperiodate (NaIO4,
1.2 equiv) in aqueous methanol at 0 ꢂC to room temperature over-
night gave the corresponding sulfoxides 8A and 8B in 89 and 87%
yields, respectively, each as a mixture of diastereomers. Treatment
of 8A or 8B with LDA (3.5 equiv) in THF at ꢀ78 ꢂC for 2 h and 0 ꢂC for
2 h followed by quenching with saturated ammonium chloride
solution afforded spiroketosulfoxide 9A or 9B, each as a mixture of
diastereomers in quantitative yield. Subsequent sulfoxide elimi-
nation of the crude products 9A and 9B in refluxing toluene in the
presence of CaCO3 for 15 h yielded the corresponding hydroxyl-
spirocyclopentenones 10A and 10B in 80 and 83% yields, re-
spectively. Eventually, hydrolysis of the butanediacetal (BDA)
Having accomplished the synthesis of (ꢀ)-pentenomycin I (1)
and (ꢀ)-epipentenomycin I (5), the syntheses of their corre-
sponding enantiomers, i.e., (þ)-pentenomycin
I (ent-1) and
(þ)-epipentenomycin I (ent-5), respectively, were straightforward
starting from ent-6 using the reaction conditions described in
Scheme 1. Yields in each step were comparable to those obtained in
the prior synthetic route starting from (2S,5S,6S)-ester 6. The
spectroscopic data and optical properties of (þ)-pentenomycin I
(ent-1) and (þ)-epipentenomycin I (ent-5) were in agreement with
those reported in the literature (Fig. 3).7
At this stage, we would like to demonstrate the synthetic ver-
satility of our synthesis by preparing some pentenomycin analogs
from common intermediates isolated from our synthetic approach
to the pentenomycins. Accordingly, spiroketosulfoxide ent-9A was
OH
OMe
O
OH
OMe
O
OMe
O
O
O
a
O
SPh
O
SPh
+
OMe
OMe
OMe
OMe
O
OMe
O
OMe
6
7A (34%)
7B (32%)
OH
O
OH
OMe
O
OH
OH
e
OMe
O
OMe
HO
HO
c
d
O
b
O
O
7A
SPh
O
(80%)
OMe
OMe
(89%)
OMe
O
OMe
O
O
O
SPh
O
8A
10A
(−)-Pentenomycin I (1)
9A
OH
OH
OMe
OH
OH
OMe
O
OMe
HO
HO
O
c
d
O
b
e
O
O
O
7B
SPh
O
(83%)
OMe
OMe
(87%)
OMe
O
OMe
O
O
O
SPh
O
8B
(−)-Epipentenomycin I (5)
10B
9B
Scheme 1. Synthesis of (ꢀ)-pentenomycin I (1) and (ꢀ)-epipentenomycin I (5). Reagents and conditions: (a) LDA, THF, ꢀ78 ꢂC, then PhS(CH2)2CHO; (b) NaIO4, MeOH, H2O; (c) LDA
(3.5 equiv), THF, ꢀ78 ꢂC, 2 h then 0 ꢂC, 2 h; (d) toluene, CaCO3, reflux, 15 h; (e) 90% TFA, 0 ꢂC, 5 h.

M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
6317
HO
the expected a-phenyl-substituted derivative ent-14A in 70% yield
OH
OH
together with 25% yield of the recovered starting material. The
reaction employing K2CO3 in THF and DMF provided low yield of
ent-14A.
a
-Phenylspirocyclopentenone ent-14A was hydrolyzed
-phenyl-
white solid in 84% yield after
O
under standard conditions to give the corresponding
pentenomycin ent-15A as
a
OMe
(+)-Pentenomycin I (ent-1)
O
a
O
O
chromatography.
MeO
Our success of the Suzuki–Miyaura coupling reaction of ent-14A
led us to further investigate the Sonogashira coupling reaction.19
The optimum conditions were found to employ PdCl2(PPh3)2, CuI,
and diisopropylamine in THF. The reactions of ent-13A with both
phenylacetylene and tert-butylacetylene were completed within
45 min and gave good yields of the corresponding coupling prod-
ucts ent-16Aa,b (Scheme 3).
HO
OH
H
OMe
ent-6
OH
O
(+)-Epipentenomycin I (ent-5)
Figure 3. Synthetic approach to ent-1 and ent-5.
3. Conclusion
subjected to the Pummerer rearrangement.16 Reaction employing
acetic anhydride led to the recovery of the starting material. Grat-
ifyingly, treatment of ent-9A with trifluoroacetic anhydride
(1.1 equiv) and ethyldiisopropylamine in acetonitrile at 0 ꢂC to
room temperature overnight, after chromatography, provided ent-
11A in 61% yield (Scheme 2). Subsequent standard hydrolysis of the
BDA-protecting group (90% aqueous TFA, 0 ꢂC, 5 h) provided
The work described in this article demonstrated the synthetic
utility of the intramolecular acylation of a-sulfinyl carbanions as an
efficient and general synthetic approach for the preparation of both
enantiomers of pentenomycin I and epipentenomycin I, starting
from readily available chiral ester (2S,5S,6S)-6 and ent-6. Syntheses
of pentenomycin analogs have been carried out via the Pummerer,
Suzuki–Miyaura, and Sonogashira reactions. Compound ent-10A, a
precursor for ent-pentenomycin I (ent-1), was employed as a
a
-phenylsulfanylpentenomycin (ent-12A) in 80% yield as colorless
crystals. Highly oxygenated cyclopentenones of type ent-11A and
ent-12A may be useful as starting materials for further synthetic
manipulation.
versatile starting material for the preparation of
-phenyl-substituted pentenomycins.
a-alkynyl- and
a
OMe
4. Experimental
4.1. General
HO
OMe
TFAA, CH3CN
Pr NEt
HO
HO
OH
OH
O
90% TFA
O
O
O
i-
0 °C
80%
2
OMe
OMe
0 °C to rt
O
PhS
O
O
1H NMR and 13C NMR were recorded on a Bruker DPX-300 or
a Bruker DPX-500 spectrometer. IR spectra were recorded either
with a Jasco A-302 or a Perkin–Elmer 683 infrared spectrometer.
Mass spectra were performed on a Thermo Finnigan Polaris Q mass
spectrometer. Microanalyses were performed with a Perkin–Elmer
Elemental analyzer 2400 CHN. High resolution MS were obtained
from either HR-TOF-MS Micromass model VQ-TOF2 or Finnigan
MAT 95 mass spectrometer. All chemicals used are of commercial
grade.
PhS
61%
PhS
ent-9A
ent-12A
ent-11A
O
Scheme 2. Preparation of ent-a-phenylsulfanylpentenomycin I (ent-12A).
Compound ent-10A has proven to be a crucial intermediate for
the synthesis of -aryl- and -alkynyl-substituted pentenomycin
derivatives by employing the Suzuki–Miyaura and Sonogashira
reactions, respectively (Scheme 3). Initially, -iodo derivative ent-
a
a
a
13A was prepared by treatment of ent-10A with I2 in the presence of
an amine base such as DMAP and pyridine. Under optimal condi-
tions, I2/pyridine in CCl4,17 ent-13A was obtained in 97% yield from
ent-10A.
4.2. (2S,5S,6S)-2-(10-Hydroxy-30-(phenylsulfanyl)propyl)-5,
6-dimethoxy-5,6-dimethyl-[1,4]dioxane-2-carboxylic acid
methyl ester (7)
The Suzuki–Miyaura coupling reaction18 of ent-13A with phe-
nylboronic acid was carried out by treatment of ent-13A with
phenylboronic acid in THF in the presence of 10 mol % PdCl2(PPh3)2
and Na2CO3 at 40 ꢂC for 15 h under an argon atmosphere to afford
General procedure A: a THF (15 mL) solution of (2S,5S,6S)-ester
6 (5.39 g, 23.00 mmol) was added slowly to a THF (25 mL) solution
OMe
OMe
OMe
HO
HO
HO
I
HO
Ph
OH
OH
O
O
O
a
b
c
O
O
O
97%
70%
84%
OMe
OMe
OMe
O
O
O
Ph
O
ent-10A
ent-13A
ent-14A
ent-15A
d
OMe
HO
HO
OH
OH
O
O
c
OMe
O
O
ent-17Aa (90%)
ent-17Ab (97%)
ent-16Aa (72%)
ent-16Ab (90%)
R
R
a, R = Ph; b, R = t-Bu
Scheme 3. Preparation of ent-15A and ent-17A. Reagents and conditions: (a) I2, pyridine, CCl4; (b) PhB(OH)2, PdCl2(PPh3)2, Na2CO3, THF, 60 ꢂC; (c) 90% TFA, 0 ꢂC, 5 h; (d) phe-
nylacetylene or tert-butylacetylene, PdCl2(PPh3), CuI, i-Pr2NH, THF, 0 ꢂC, 45 min.

6318
M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
of LDA [(28.75 mmol), prepared by reacting N,N-diisopropylamine
(4.53 mL, 32.2 mmol) with n-BuLi (1.35 M in hexane, 22.0 mL,
28.75 mmol)] at ꢀ78 ꢂC. The mixture was stirred at ꢀ78 ꢂC for 2 h.
To this solution was added a THF (5.75 mL) solution of 3-phenyl-
sulfanylpropanal [freshly prepared by reacting of Et3N (4.0 mL,
28.75 mmol), thiophenol (4.57 mL, 36.0 mmol) with acrolein
(1.90 mL, 28.75 mmol)]. The resulting mixture was stirred at ꢀ78 ꢂC
for 2 h and quenched with saturated aqueous NH4Cl solution
(30 mL). Layers were separated and the aqueous phase was
extracted with ethyl acetate (3ꢃ25 mL). The combined organic
layers were washed with water, brine, and dried over anhydrous
Na2SO4. The organic phase was concentrated (aspirator then in
vacuo) to give a crude pale yellow liquid, which was purified by
column chromatography (silica gel, 25% ethyl acetate in hexanes).
The less polar fraction was 7A (3.129 g, 34% yield): 1H NMR
CH2), 2.96–2.85 (m, 1H, CHH–CH2), 1.56–1.49 (m, 3H, CH–CH2 and
29
br OH), 1.24 (s, 3H, CH3), 1.20 (s, 3H, CH3). [
a
]
D
ꢀ67.0 (c 1.76, CHCl3).
4.4. (2S,5S,6S,10S)-2-(10-Hydroxy-30-(phenylsulfinyl)propyl)-
5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane-2-carboxylic acid
methyl ester (8A)
General procedure B: a solution of (2S,5S,6S,10S)-7A (3.00 g,
7.48 mmol) in methanol (36 mL) was added dropwise to a suspen-
sion of NaIO4 (0.942 g, 8.976 mmol) in water (10 mL) at 0 ꢂC. The
resulting mixture was stirred at 0 ꢂC to room temperature overnight.
The precipitate of NaIO3 was filtered and washed several times with
ethyl acetate. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (3ꢃ20 mL). The combined organic
layers were washed with water (20 mL) and brine (20 mL), and dried
over anhydrous Na2SO4. Filtration followed by evaporation (aspira-
tor then in vacuo) gave a yellow liquid of the crude product, which
was purified by column chromatography (silica gel, 80% ethyl acetate
in hexanes) to furnish a pale yellow liquid of (2S,5S,6S,10S)-8A
(2.776 g, 89% yield) as a 1:1 mixture of two diastereomers. 1H NMR
(300 MHz, CDCl3):
d
7.28–7.00 (m, 5H, ArH), 3.98 (d, J¼11.6 Hz, 1H,
C–CHH), 3.96–3.89 (m, 1H, C–CH), 3.86 (d, J¼11.6 Hz, 1H, C–CHH),
3.53 (s, 3H, CO2CH3), 3.15 (s, 3H, OCH3), 3.12 (s, 3H, OCH3), 3.10–3.05
(m, 2H, CHH–CH2 and br OH), 2.90–2.78 (m, 1H, CHH–CH2), 1.50–
1.35 (m, 1H, CH–CHH), 1.35–1.20 (m, 4H, CH3, CH–CHH), 1.20 (s, 3H,
CH3). 13C NMR (75 MHz, CDCl3):
d
171.7 (C]O), 135.6 (C), 129.2
(300 MHz, CDCl3, data are reported for both diastereomers): d 7.60–
(2ꢃCH), 128.7 (2ꢃCH), 125.8 (CH), 99.7 (C), 97.6 (C), 76.1 (CH), 72.6
(CH), 56.4 (CH2), 52.1 (CH), 50.2 (CH), 48.0 (CH3), 30.0 (CH3), 28.4
(CH3), 17.5 (CH3), 17.4 (CH3). IR (neat): nmax 3480 m, 1739 s, 1584 m,
1482 s,1375 s,1148 s,1037 s, 740 m, 692 m cmꢀ1. MS: m/z (% relative
intensity): 400 (Mþ, 0.6), 337 (46), 143 (100), 136 (81), 123 (62), 110
7.42 (m, 2ꢃ5H, ArH), 4.12 (d, J¼11.5 Hz, 1H, OCHH), 4.04 (d,
J¼11.5 Hz, 1H, OCHH), 3.81 (d, J¼11.5 Hz, 1H, OCHH), 3.77 (d,
J¼11.5 Hz, 1H, OCHH), 3.69–3.61 (br s, 4H, OCH3 and CHOH), 3.62 (s,
3H, OCH3), 3.30 (br, 1H, OH), 3.16 (s, 3H, OCH3), 3.14 (s, 3H, OCH3),
3.12 (s, 3H, OCH3), 3.07 (s, 3H, OCH3), 3.20–3.02 (m, 3ꢃ1H, CHH–CH2
and CHOH), 2.85 (br, 1H, OH), 2.83–2.65 (m, 2ꢃ1H, CHH–CH2), 1.80–
(58), 93 (45). HRMS (ESI-TOF) calcd for C19H28O7SNa: 423.1453;
29
found: 423.1454. [
a
]
þ139.7 (c 0.9, CHCl3). The more polar fraction
1.40 (m, 2ꢃ2H, CH2–CH),1.21 (s, 2ꢃ3H, CH3),1.17 (s, 2ꢃ3H, –CH3). 13
C
D
was 7B (2.945 g, 32% yield): 1H NMR (300 MHz, CDCl3):
d
7.20–7.06
NMR (75 MHz, CDCl3): d 171.4 (C]O), 171.3 (C]O), 143.1 (C), 142.7
(m, 5H, ArH), 4.05 (d, J¼11.7 Hz, 1H, CHH), 3.76 (dd, J¼8.8, 3.9 Hz,
1H, CHO), 3.69 (s, 3H, CO2CH3), 3.65 (d, J¼11.7 Hz, 1H, CHH), 3.19 (s,
2ꢃ3H, OCH3), 3.11–3.03 (m, 1H, CHH–CH2), 2.96–2.85 (m, 1H, CHH–
CH2), 2.10–1.85 (br s, 1H, OH), 1.61–1.49 (m, 2H, CH–CH2), 1.24 (s,
(C), 130.8 (2ꢃCH), 129.06 (2ꢃCH), 129.02 (2ꢃCH), 123.9 (2ꢃCH),
123.8 (2ꢃCH), 99.64 (C), 99.61 (C), 97.69 (C), 97.67 (C), 75.6 (C), 75.4
(C), 73.7 (CH), 73.3 (CH), 58.0 (CH2), 57.5 (CH2), 54.0 (CH2), 53.9
(CH2), 53.3 (2ꢃC), 52.3 (CH3), 52.1 (CH3), 50.2 (2ꢃCH3), 48.0 (CH3),
47.9 (CH3), 23.2 (CH2), 22.8 (CH2), 17.5 (CH3), 17.4 (CH3). IR (neat):
nmax 3364 m,1738 s,1732 s,1445 s,1374 s,1251 s,1146 s,1046 m, 883
s, 751 m, 692 m cmꢀ1. MS: m/z (% relative intensity): 416 (Mþ, 0.3),
143 (87), 125 (65), 109 (64), 93 (48), 83 (59), 73 (100). HRMS (ESI-
TOF) calcd for C19H28O8SNa: 439.1403; found: 439.1390.
3H, CH3), 1.20 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 171.8 (C]O),
135.9 (C), 129.4 (2ꢃCH), 128.8 (2ꢃCH), 126.0 (CH), 99.4 (C), 97.9 (C),
75.3 (C), 73.3 (CH), 59.5 (CH2), 52.1 (CH3), 50.5 (CH3), 48.2 (CH3),
30.4 (CH2), 30.3 (CH2), 17.7 (CH3), 17.6 (CH3). IR (neat): nmax 3480 m,
1739 s, 1634 w, 1585 m, 1482 m, 1440 s, 1252 s, 1147 s, 1101 s, 1050 s,
1037 m cmꢀ1. MS: m/z (% relative intensity): 400 (Mþ, 0.2), 251 (47),
220 (45),192 (49),143 (100),136 (92),123 (76),110 (82). HRMS (ESI-
4.5. (2S,5S,6S,10R)-2-(10-Hydroxy-30-(phenylsulfinyl)propyl)-
5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane-2-carboxylic acid
methyl ester (8B)
29
TOF) calcd for C19H28O7SNa: 423.1453; found: 423.1450. [
(c 1.75, CHCl3).
a]
þ60.6
D
4.3. (2R,5R,6R)-2-(10-Hydroxy-30-(phenylsulfanyl)propyl)-
5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane-2-carboxylic acid
methyl ester (ent-7)
According to the general procedure B, a solution of
(2S,5S,6S,10R)-7B (2.019 g, 5.00 mmol) in methanol (24.00 mL) was
treated with NaIO4 (0.634 g, 6.0 mmol) in water (24 mL) at 0 ꢂC to
room temperature overnight to give a crude product, which was
purified by column chromatography (silica gel, 80% ethyl acetate in
hexanes) to furnish a yellow syrup of (2S,5S,6S,10R)-8B (1.828 g, 87%
yield) as 1:1 mixture of diastereomers. 1H NMR (300 MHz, CDCl3,
According to the general procedure A, a THF (15 mL) solution of
(2R,5R,6R)-ester ent-6 (4.683 g, 20.0 mmol) was treated with a THF
(20 mL) solution of LDA (25 mmol) at ꢀ78 ꢂC. The resulting solution
was reacted with a THF (5 mL) solution of 3-phenylsulfanyl-
propanal [freshly prepared from Et3N (3.48 mL, 25.0 mmol), thio-
phenol (3.98 mL, 31.25 mmol) and acrolein (1.65 mL, 25.0 mmol)].
The crude product was purified by column chromatography (silica
gel, 25% ethyl acetate in hexanes) to give two separable dia-
stereomers of ent-7. A less polar fraction was ent-7A (2.637 g, 33%
data are reported for both diastereomers):
d
7.58–7.31 (m, 2ꢃ5H,
ArH), 4.15 (d, J¼11.5 Hz, 1H, O–CHH), 4.12 (d, 1H, J¼11.5 Hz, O–CHH),
3.71 (s, 3H, OCH3), 3.69 (m, 2ꢃ1H, CH–OH), 3.68 (s, 3H, CO2CH3),
3.56 (d, J¼11.5 Hz, 2ꢃ1H, OCHH), 3.18 (s, 3H, OCH3), 3.14 (s, 2ꢃ3H,
OCH3), 3.10 (s, 3H, OCH3), 3.10–3.01 (m, 2ꢃ1H, CHH–CH2), 2.90–
2.62 (m, 2ꢃ2H, CHH–CH and br OH), 2.20–1.91 (m, 2ꢃ1H, CHH–CH),
1.69–1.61 (m, 2ꢃ1H, CH–CHH), 1.21 (s, 3H, CH3), 1.13 (s, 3H, CH3),
yield): 1H NMR (300 MHz, CDCl3):
d 7.28–7.00 (m, 5H, ArH), 3.98 (d,
J¼11.6 Hz, 1H, C–CHH), 3.96–3.89 (m, 1H, C–CH), 3.86 (d, J¼11.6 Hz,
1H, C–CHH), 3.53 (s, 3H, CO2CH3), 3.15 (s, 3H, –OCH3), 3.12 (s, 3H,
OCH3), 3.10–3.05 (m, 1H, CHH–CH2), 2.90–2.78 (m, 2H, CHH–CH2
1.19 (s, 3H, CH3), 1.17 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 172.4
(C]O), 172.1 (C]O), 143.1 (C), 142.0 (C), 131.0 (CH), 130.9 (CH),
129.2 (2ꢃCH), 129.1 (2ꢃCH), 124.2 (2ꢃCH), 124.0 (2ꢃCH), 99.37 (C),
99.32 (C), 97.9 (2ꢃC), 75.0 (C), 74.9 (C), 74.1 (CH), 73.8 (CH), 58.6
(CH2), 58.2 (CH2), 54.7 (CH2), 53.7 (CH2), 52.3 (CH3), 52.2 (CH3),
50.35 (2ꢃCH3), 48.1 (CH3), 48.0 (CH3), 25.2 (CH2), 24.7 (CH2), 17.64
(2ꢃCH3), 17.58 (2ꢃCH3). IR (neat): nmax 3554 s, 2923 s, 2583 s, 1726
s, 1455 s, 1377 s, 1303 m, 1253 m, 1145 s cmꢀ1. MS: m/z (% relative
intensity): 416 (Mþ, 0.1), 143 (78),141.2 (78),125 (55), 115 (100), 109
and br OH), 1.50–1.35 (m, 1H, CH–CHH), 1.35–1.20 (m, 4H, CH3, CH–
29
CHH), 1.20 (s, 3H, CH3). [
a]
ꢀ110.6 (c 0.98, CHCl3). A more polar
D
fraction was ent-7B (liquid, 2.482 g, 31% yield): 1H NMR (300 MHz,
CDCl3):
d
7.20–7.06 (m, 5H, ArH), 4.05 (d, J¼11.7 Hz, 1H, CHH), 3.76
(dd, J¼8.8, 3.9 Hz, 1H, C–CH), 3.66 (s, 3H, CO2CH3), 3.65 (d,
J¼11.7 Hz, 1H, CHH), 3.19 (s, 2ꢃ3H, OCH3), 3.11–3.03 (m, 1H, CHH–

M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
6319
(48), 83 (74). HRMS (ESI) calcd for C19H28O8SNa: 439.1403; found:
439.1400.
(d, J¼15.7 Hz,1H, CHOH),1.65 (br s,1H, OH),1.32 (s, 3H, CH3),1.25 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3):
205.9 (C]O), 140.2 (C), 131.5
d
(CH), 129.5 (2ꢃCH), 124.1 (2ꢃCH), 99.5 (C), 97.9 (C), 77.0 (C), 71.9
(CH), 69.5 (CH), 57.1 (CH2), 49.1 (CH3), 48.2 (CH3), 26.5 (CH2), 18.1
(CH3), 17.7 (CH3). IR (CHCl3): nmax 3290 w, 1755 s, 1445 m, 1146 s,
1114 s, 1032 m, 969 m cmꢀ1. MS: m/z (% relative intensity): 384 (Mþ,
4.6. (2R,5R,6R,10R)-2-(10-Hydroxy-30-(phenylsulfinyl)propyl)-
5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane-2-carboxylic acid
methyl ester (ent-8A)
0.7), 227 (66), 195 (61), 126 (53), 115 (99), 101 (55), 73 (100). HRMS
29
According to the general procedure B,
a
solution of
(ESI-TOF) calcd for C18H24O7SNa: 407.1140; found: 407.1140. [a]
D
(2R,5R,6R,10R)-ent-7A (2.082 g, 5.20 mmol) in methanol (25 mL)
was treated with NaIO4 (0.654 g, 1.39 mmol) in water (10 mL) at
0 ꢂC to room temperature overnight to give a crude product, which
was purified by column chromatography (silica gel, 80% ethyl ace-
tate in hexanes) to furnish a pale yellow syrup of (2R,5R,6R,10R)-ent-
8A (1.832 g, 87% yield) as a mixture of diastereomers. The 1H NMR
spectrum was identical to that of 8A: 1H NMR (300 MHz, CDCl3,
þ375.0 (c 0.60, CHCl3). Fraction II (more polar) was obtained as
a pale yellow viscous liquid (0.716 g, 43% yield; a mixture of two
diastereomers): 1H NMR (300 MHz, CDCl3, data are reported for
both diastereomers):
d 7.61–7.42 (m, 10H, ArH), 4.19 (br, 1H), 3.95
(br, 1H), 3.95 (d, J¼12.3 Hz, 1H), 3.78–3.73 (m, 3H), 3.44 (dd, J¼12.2,
10.4 Hz, 2H), 3.19 (s, 3H, OCH3), 3.18 (s, 3H, OCH3), 3.16 (s, 3H,
OCH3), 2.89 (s, 3H, OCH3), 2.81 (d, J¼15.5 Hz, 1H), 2.42 (br d,
J¼15.5 Hz, 1H), 1.51 (dd, J¼13.7, 10.0 Hz, 2H), 1.40–1.10 (br, 2H, OH),
1.25 (s, 3H, CH3), 1.21 (s, 3H, CH3), 1.17 (s, 3H, CH3), 1.14 (s, 3H, CH3).
data are reported for both diastereomers):
d
7.60–7.42 (m, 2ꢃ5H,
ArH), 4.12 (d, J¼11.5 Hz, 1H, OCHH), 4.04 (d, J¼11.5 Hz, 1H, OCHH),
3.81 (d, J¼11.5 Hz, 1H, OCHH), 3.77 (d, J¼11.5 Hz, 1H, OCHH), 3.69 (s,
3H, OCH3), 3.62 (s, 4H, OCH3 and CHOH), 3.16 (s, 4H, OCH3 and
CHOH), 3.14 (s, 3H, OCH3), 3.12 (s, 3H, OCH3), 3.07 (s, 3H, OCH3), 3.02
(m, 2ꢃ1H, CHH–CH2), 2.83–2.75 (m, 2ꢃ1H, –CHH–CH2), 2.70 (br s,
2ꢃ1H, OH), 1.80–1.40 (m, 2ꢃ2H, CH2–CH), 1.21 (s, 2ꢃ3H, CH3), 1.17
(s, 2ꢃ3H, CH3).
13C NMR (75 MHz, CDCl3):
d 205 (C]O), 203.8 (C]O), 142.5 (C), 138
(C), 131.4 (CH), 131.0 (2ꢃCH), 129.2 (2ꢃCH), 128.9 (2ꢃCH), 124.7
(CH), 123.8 (2ꢃCH), 99.4 (C), 99.1 (C), 98.2 (C), 97.9 (C), 76.6 (C), 75.4
(C), 74.4 (CH), 72.7 (CH), 69.1 (CH), 63.3 (CH), 57.3 (CH2), 56.5 (CH2),
49.5 (CH3), 48.7 (CH3), 48.3 (CH3), 48.1 (CH3), 31.4 (CH2), 23.2 (CH2),
18.2 (2ꢃCH3), 17.7 (CH3), 17.6 (CH3). IR (CHCl3): nmax 3368 w, 3028
m, 1755 s, 1445 m, 1147 s, 1112 s, 1036 m cmꢀ1. MS: m/z (% relative
intensity): 384 (Mþ, 0.4), 227 (43), 195 (56), 125 (77), 115 (74), 111
(88), 109 (48), 99 (61), 97 (43), 73 (100). HRMS (ESI-TOF) calcd for
4.7. (2R,5R,6R,10S)-2-(10-Hydroxy-30-(phenylsulfinyl)propyl)-
5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane-2-carboxylic acid
methyl ester (ent-8B)
C18H24O7SNa: 407.1132; found: 407.1108.
According to the general procedure B, a solution of (2R,5R,6R,10S)-
ent-7B (2.403 g, 6.00 mmol) in methanol (38 mL) was treated with
NaIO4 (0.755 g, 1.60 mmol) and water (10 mL) at 0 ꢂC to room tem-
perature overnight to give a pale yellow syrup of a crude product,
which was purified by column chromatography (silica gel, 80% ethyl
acetate in hexanes) to furnish a pale yellow syrup of (2R,5R,6R,10S)-
ent-8B (2.125 g, 85% yield) as a mixture of diastereomers. The 1H
NMR spectrum was identical to that of 8B: 1H NMR (300 MHz, CDCl3,
4.9. (2S,5S,6S,50R)-50-Hydroxy-20-oxo-30-phenylsulfinyl
spirocyclopentane-5,6-dimethoxy-5,6-dimethyl-[1,4]-
dioxane (9B)
According to the general procedure C, a THF (10 mL) solution of
(2S,5S,6S,50R)-8B (1.611 g, 4.45 mmol) was added slowly to a cooled
(ꢀ78 ꢂC) THF (10 mL) solution of LDA (15.60 mmol). After stirring
at ꢀ78 ꢂC for 2 h, the mixture was stirred at 0 ꢂC for 2 h and
quenched with saturated aqueous NH4Cl solution (40 mL) and
extracted with ethyl acetate (3ꢃ30 mL). The organic phase was
washed with water (30 mL), brine (20 mL), and dried over anhy-
drous Na2SO4. The crude product obtained was purified by column
chromatography (silica gel, 30–65% ethyl acetate in hexanes) to
give two fractions of 9B. Fraction I (less polar) was obtained as
a white solid of (0.267 g, 18% yield, 165–168 ꢂC; a single dia-
data are reported for both diastereomers):
d
7.51–7.40 (m, 2ꢃ5H,
ArH), 4.22 (d, J¼11.5 Hz, 1H, OCHH), 4.19 (d, J¼11.5 Hz, 1H, OCHH),
3.78 (s, 3H, CO2CH3), 3.76 (m, 2ꢃ1H, CHOH), 3.75 (s, 3H, CO2CH3),
3.63 (d, 2ꢃ1H, J¼11.5 Hz, OCHH), 3.25 (s, 3H, OCH3), 3.21 (s, 2ꢃ3H,
OCH3), 3.17 (s, 3H, OCH3), 3.05–2.75 (m, 2ꢃ2H, CH2–CH2 and br OH),
2.88 (m, 2ꢃ1H, CHH–CH), 2.04–1.98 (m, 2ꢃ1H, CHH–CH), 1.76–1.68
(m, 2ꢃ1H, CH–CHH), 1.28 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.26 (s, 3H,
CH3), 1.24 (s, 3H, CH3).
stereomer): 1H NMR (300 MHz, CDCl3):
d 7.58–7.34 (m, 5H, ArH),
4.19 (dd, J¼5.0, 3.0 Hz, 1H, CHOH), 4.03 (d, J¼11.9 Hz, 1H, OCHH),
3.74 (d, J¼11.9 Hz,1H, OCHH), 3.56 (t, J¼9.1 Hz,1H, CH2–CH), 3.28 (s,
3H, OCH3), 3.48 (s, 3H, OCH3), 2.56 (ddd, J¼14.5, 9.1, 5.0 Hz, 1H,
CHH), 1.80 (ddd, J¼15.6, 11.9, 3.0 Hz,1H, CHH), 1.6 (br s, 1H, OH), 1.36
4.8. (2S,5S,6S,50S)-50-Hydroxy-20-oxo-30-phenylsulfinyl
spirocyclopentane-5,6-dimethoxy-5,6-dimethyl-[1,4]-
dioxane (9A)
(s, 3H, CH3), 1.34 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 207.3
General procedure C: a THF (11 mL) solution of (2S,5S,6S,50S)-8A
(1.806 g, 5.00 mmol) was slowly added to a cooled (ꢀ78 ꢂC) THF
(12 mL) solution of LDA [(17.50 mmol), prepared by reacting N,N-
diisopropylamine (2.76 mL, 19.6 mmol) with n-BuLi (1.35 M in
hexane, 13.35 mL, 17.5 mmol)]. The reaction mixture was stirred
at ꢀ78 ꢂC for 2 h and at 0 ꢂC for 2 h. The resulting dark-orange
solution was quenched with saturated aqueous NH4Cl solution
(40 mL) and extracted with ethyl acetate (3ꢃ30 mL). The organic
phase was washed with water (30 mL), brine (20 mL), and dried
over anhydrous Na2SO4. The crude product obtained was purified
by column chromatography (silica gel, 30–65% ethyl acetate in
hexanes) to give two fractions of 9A. Fraction I (less polar) was
obtained as a white solid (0.317 g, 19% yield, mp 172–175 ꢂC; a sin-
(C]O), 141.3 (C), 131.2 (CH), 129.3 (2ꢃCH), 123.8 (2ꢃCH), 100.6 (C),
99.3 (C), 81.1 (C), 70.9 (CH), 67.7 (CH), 58.3 (CH2), 48.9 (CH3), 48.1
(CH3), 21.5 (CH2), 18.6 (CH3), 18.3 (CH3). IR (CHCl3): nmax 3288 m,
1749 s, 1460 m, 1377 m, 1145 m, 1032 m cmꢀ1. MS: m/z (% relative
intensity): 384 (Mþ, 0.5), 153 (57), 149 (54), 126 (71), 111 (90), 109
(55), 73 (100). HRMS (ESI-TOF) calcd for C18H24O7Na: 407.1140;
29
found: 407.1140. [
a]
þ305.9 (c 0.35, CHCl3). Fraction II (more
D
polar) was obtained as a pale yellow liquid (0.654 g, 44% yield;
mixture of two diastereomers): 1H NMR (300 MHz, CDCl3, data are
reported for both diastereomers):
d 7.63–7.45 (m, 10H, ArH), 4.20
(dd, J¼10.1, 6.0 Hz, 1H), 3.74–3.65 (m, 3H), 3.42–3.30 (m, 1H), 3.30
(s, 3H, OCH3), 3.27–3.05 (m, 5H), 3.23 (s, 3H, OCH3), 3.21 (s, 3H,
OCH3), 3.13 (s, 3H, OCH3), 2.71–2.65 (m, 1H), 2.56–2.40 (m, 1H),
2.39–2.29 (m, 1H), 1.90–1.74 (m, 1H), 1.31 (s, 3H, CH3), 1.28 (s, 3H,
CH3), 1.23 (s, 3H, CH3), 1.21 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
gle diastereomer): 1H NMR (300 MHz, CDCl3):
d 7.59–7.54 (m, 5H,
ArH), 4.25 (d, J¼8.8 Hz, 1H, C–CHH), 4.00–3.95 (m, 2H, C–CHH and
CHH–CHOH), 3.74 (d, J¼11.6 Hz, 1H, SOCH), 3.28 (s, 3H, OCH3), 3.15
(s, 3H, OCH3), 2.72 (ddd, J¼15.7, 11.6, 4.3 Hz, 1H, CHH–CHOH), 2.01
d
205.3 (C]O), 204.8 (C]O), 142.6 (C), 139.6 (C), 131.9 (CH), 131.2
(CH), 129.3 (2ꢃCH), 129.1 (2ꢃCH), 125.2 (2ꢃCH), 123.9 (2ꢃCH),

6320
M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
100.2 (C), 99.7 (C), 98.6 (C), 98.4 (C), 78.3 (C), 75.6 (C), 71.0 (CH),
70.2 (CH), 69.1 (CH), 66.8 (CH), 58.1 (CH2), 57.5 (CH2), 49.6 (CH3),
48.9 (CH3), 48.3 (CH3), 48.0 (CH3), 25.8 (CH2), 22.9 (CH2), 18.3 (CH3),
18.1 (CH3), 17.9 (CH3), 17.8 (CH3). IR (CHCl3): nmax 3386 m, 1754 s,
1445 m, 1376 m, 1147 s, 1112 s, 1055 m, 1036 m cmꢀ1. MS: m/z (%
relative intensity): 385 (Mþþ1, 0.6), 227 (61), 195 (47), 126 (75), 115
(79), 109 (51), 69 (100). HRMS (ESI-TOF) calcd for C18H24O7Na:
407.1140; found: 407.1136.
was refluxed at 110 ꢂC for 10 h under an argon atmosphere. After
removal of toluene (aspirator then in vacuo), the residue was pu-
rified by column chromatography (silica gel, 23% ethyl acetate in
hexanes) to give a single diastereomer of (2S,5S,6S,50S)-10A as
a white solid (0.205 g, 80% yield, mp 96–99 ꢂC). 1H NMR (300 MHz,
CDCl3):
d
7.63 (dd, J¼6.1 Hz, 1H, ]CHb), 6.28 (dd, J¼6.1 Hz, 1H,
]CHa), 4.59 (s, 1H, CCH), 4.22 (d, J¼10.9 Hz, 1H, CHH), 3.46 (s, 3H,
OCH3), 3.34 (d, J¼10.9 Hz, 1H, CHH), 3.31 (s, 3H, OCH3), 1.34 (s, 3H,
CH3), 1.33 (br s, 1H, OH), 1.31 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
4.10. (2R,5R,6R,50R)-50-Hydroxy-20-oxo-30-phenylsulfinyl
spirocyclopentane-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane
(ent-9A)
d 203.1 (C]O), 161.1 (CH), 133.6 (CH), 133.9 (CH), 100.9 (C), 99.98
(C), 77.1 (C), 63.6 (CH2), 48.6 (CH3), 48.0 (CH3), 18.78 (CH3), 18.73
(CH3). IR (Nujol): nmax 3501 m, 1728 s, 1596 w, 1463 m, 1150 s, 1114 s,
1075 s cmꢀ1. MS: m/z (% relative intensity): 258 (Mþ, 0.8), 195 (76),
110 (71), 109 (20), 101 (37), 89 (36), 82 (52), 73 (100), 55 (23), 53
According to the general procedure C, a THF (10 mL) solution of
(2R,5R,6R,50R)-ent-8A (1.695 g, 4.69 mmol) was treated with a THF
(12 mL) solution of LDA (16.42 mmol) to provide a crude product,
which was purified by column chromatography (silica gel, 30–65%
ethyl acetate in hexanes) to give two fractions of ent-9A. Fraction I
(less polar) was obtained as a white solid (0.3129 g, 20% yield, mp
174–175 ꢂC; a single diastereomer): 1H NMR (300 MHz, CDCl3):
(23). HRMS (ESI-TOF) calcd for C12H18O6Na: 281.1001; found:
29
281.1002. [
a
]
þ58.6 (c 1.33, CHCl3).
D
4.13. (2S,5S,6S,50R)-50-Hydroxy-20-oxospirocyclopent-30-
ene-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane (10B)
d
7.59–7.54 (m, 5H, ArH), 4.25 (d, J¼8.8 Hz, 1H, C–CHH), 4.00–3.95
A
mixture of diastereomers of (2S,5S,6S,50R)-9B (0.365 g,
(m, 1H, C–CHH), 3.74 (d, J¼11.6 Hz, 1H, S(O)CH), 4.00–3.90 (m, 1H,
0.95 mmol) and anhydrous CaCO3 (3.0 g) in dry toluene (15 mL)
was refluxed at 110 ꢂC for 10 h under an argon atmosphere. After
removal of toluene (aspirator then in vacuo), the residue was pu-
rified by column chromatography (silica gel, 27% ethyl acetate in
hexanes) to give a single diastereomer of (2S,5S,6S,50R)-10B as
a colorless liquid (0.201 g, 83% yield). 1H NMR (300 MHz, CDCl3):
CHH–CHOH), 3.28 (s, 3H, OCH3), 3.15 (s, 3H, OCH3), 2.72 (ddd,
J¼15.7, 11.6, 4.3 Hz, 1H, CHH–CHOH), 2.01 (d, J¼15.7 Hz, 1H, CHOH),
29
1.75 (br s, 1H, OH), 1.32 (s, 3H, CH3), 1.25 (s, 3H, CH3). [
a
]
D
ꢀ380.9 (c
0.31, CHCl3). Fraction II (more polar) was obtained as a yellow liquid
(0.655 g, 42% yield; mixture of two diastereomers): 1H NMR
(300 MHz, CDCl3, data are reported for both diastereomers):
d
7.61–
d
7.43 (dd, J¼5.9 Hz, 1H, ]CHb), 6.14 (dd, J¼5.9 Hz, 1H, ]CHa), 4.87
7.42 (m, 2ꢃ5H, ArH), 4.15 (br, 1H), 3.95 (br, 1H), 3.81 (d, J¼12.3 Hz,
1H), 3.80–3.61 (m, 3H), 3.44 (dd, J¼12.2, 10.4 Hz, 2H), 3.19 (s, 3H,
OCH3), 3.18 (s, 3H, OCH3), 3.16 (s, 3H, OCH3), 2.89 (s, 3H, OCH3), 2.81
(d, J¼14.5 Hz, 1H), 2.42 (d, J¼15.5 Hz, 1H), 1.51 (dd, J¼13.7, 10.0 Hz,
2H), 1.30–1.11 (br, 2ꢃ1H, OH), 1.25 (s, 3H, CH3), 1.21 (s, 3H, CH3), 1.17
(s, 3H, CH3), 1.14 (s, 3H, CH3).
(s, 1H, CCH), 4.11 (d, J¼10.9 Hz, 1H, CHH), 3.77 (d, J¼10.9 Hz, 1H,
CHH), 3.41 (s, 3H, OCH3), 3.36 (s, 3H, OCH3), 3.32 (br s, 1H, OH), 1.45
(s, 3H, CH3), 1.36 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 202.4
(C]O), 160.5 (CH), 132.9 (CH), 100.58 (C), 100.52 (C), 81.1 (C), 79.9
(CH), 60.3 (CH2), 49.2 (CH3), 48.4 (CH3), 18.8 (CH3), 18.6 (CH3). IR
(CHCl3): nmax 3565 w, 1725 s, 1597 w, 1456 w, 1376 m, 1153 s, 1141
s cmꢀ1. MS: m/z (% relative intensity): 258 (Mþ, 0.8), 110 (71), 89
(36), 82 (52), 74 (100). HRMS (ESI-TOF) calcd for C12H18O6Na:
281.1001; found: 281.1001. [
4.11. (2R,5R,6R,50S)-50-Hydroxy-20-oxo-30-phenylsulfinyl
spirocyclopentane-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane
(ent-9B)
29
a
]
þ76.2 (c 0.18, CHCl3).
D
4.14. (2R,5R,6R,50R)-50-Hydroxy-20-oxospirocyclopent-30-
ene-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane (ent-10A)
According to the general procedure C, a THF (10 mL) solution of
(2R,5R,6R,50S)-ent-8B (2.080 g, 5.00 mmol) was treated with a THF
(12 mL) solution of LDA (17.47 mmol) to provide a crude product,
which was purified by column chromatography (silica gel, 30–65%
ethyl acetate in hexanes) to give two fractions of ent-9B. Fraction I
(less polar)wasobtained asawhitesolid (0.439 g,17%yield, mp167–
A mixture of (2R,5R,6R,50R)-ent-9A (0.351 g, 0.91 mmol) and
anhydrous CaCO3 (3.0 g) was refluxed in dry toluene (15 mL) for
10 h under an argon atmosphere. The crude product was purified
by column chromatography (silica gel, 23% ethyl acetate in hex-
anes) to give a single diastereomer of (2R,5R,6R,50R)-ent-10A as
a white solid (0.189 g, 80% yield, mp 97–101 ꢂC). 1H NMR (300 MHz,
169 ꢂC; a single diastereomer): 1H NMR (300 MHz, CDCl3):
d 7.58–
7.34 (m, 5H, ArH), 4.19 (dd, J¼5.0, 3.0 Hz, 1H, CHOH), 4.03 (d,
J¼11.9 Hz,1H, OCHH), 3.74 (d, J¼11.9 Hz,1H, OCHH), 3.56 (t, J¼9.1 Hz,
1H, CH2–CH), 3.28 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 2.56 (ddd, J¼14.5,
CDCl3):
d
7.63 (dd, J¼6.1 Hz, 1H, ]CHb), 6.28 (dd, J¼6.1 Hz, 1H,
]CHa), 4.59 (s, 1H, CCH), 4.30 (d, J¼10.9 Hz, 1H, CHH), 3.52 (s, 3H,
9.1, 5.0 Hz,1H, CHH),1.80 (ddd, J¼15.6,11.9, 3.0 Hz,1H, CHH),1.68 (br,
OCH3), 3.40 (d, J¼10.9 Hz, 1H, CHH), 3.39 (s, 3H, OCH3), 1.80 (br s,
29
29
1H, OH), 1.36 (s, 3H, CH3), 1.34 (s, 3H, CH3). [
a
]
ꢀ306.86 (c 0.35,
1H, OH), 1.42 (s, 3H, CH3), 1.41 (s, 3H, CH3). [
a
]
ꢀ52.8 (c 0.175,
D
D
CHCl3). Fraction II (more polar) was obtained as a pale yellow liquid
CHCl3).
(0.712 g, 43% yield; a mixture of diastereomers): 1H NMR (300 MHz,
CDCl3, data are reported for both diastereomers):
d
7.63–7.45 (m,
4.15. (2R,5R,6R,50S)-50-Hydroxy-20-oxospirocyclopent-30-
ene-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane (ent-10B)
2ꢃ5H, ArH), 4.20 (dd, J¼10.1, 6.0 Hz, 1H), 3.75–3.68 (m, 2H), 3.37 (d,
J¼11.9 Hz, 1H), 3.30 (s, 3H, OCH3), 3.23 (s, 3H, OCH3), 3.25–3.18 (m,
2H), 3.21 (s, 3H, OCH3), 3.13 (s, 3H, OCH3), 3.10 (d, J¼11.9 Hz,1H), 3.09
(d, J¼16.2 Hz, 1H), 2.71–2.65 (m, 1H), 2.56–2.40 (m, 1H), 2.39–2.29
(m,1H), 2.81–1.94 (m,1H),1.80–1.78 (br, 2ꢃ1H, OH),1.31 (s, 3H, CH3),
1.28 (s, 3H, CH3), 1.23 (s, 3H, CH3), 1.21 (s, 3H, CH3).
A mixture of (2R,5R,6R,50S)-ent-9B (0.2176 g, 0.57 mmol) and
anhydrous CaCO3 (3.0 g) in dry toluene (10 mL) was refluxed at
110 ꢂC for 10 h under an argon atmosphere. The crude product was
purified by column chromatography (silica gel, 27% ethyl acetate in
hexanes) to give a single diastereomer of (2R,5R,6R,50S)-ent-10B as
4.12. (2S,5S,6S,50S)-50-Hydroxy-20-oxospirocyclopent-30-
a colorless liquid (0.1227 g, 84%). 1H NMR (300 MHz, CDCl3):
d 7.50
ene-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane (10A)
(dd, J¼5.9 Hz, 1H, ]CHb), 6.23 (dd, J¼5.9 Hz, 1H, ]CHa), 4.95 (s, 1H,
CCH), 4.18 (d, J¼10.9 Hz,1H, CHH), 3.85 (d, J¼10.9 Hz,1H, CHH), 3.49
A
mixture of diastereomers of (2S,5S,6S,50S)-9A (0.385 g,
1.00 mmol) and anhydrous CaCO3 (3.0 g) in dry toluene (15 mL)
(s, 3H, OCH3), 3.44 (s, 3H, OCH3), 1.80 (br s, 1H, OH), 1.45 (s, 3H, CH3),
29
1.36 (s, 3H, CH3). [
a
]
ꢀ74.1 (c 0.2053, CHCl3).
D

M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
6321
4.16. (L)-Pentenomycin I (1)
1.00 mmol) in acetonitrile (5 mL) followed by the addition of dii-
sopropylethylamine (0.11 mL, 0.8 mmol). After stirring at room
temperature overnight (12 h), a dark-brown solution was quenched
with 1 M HCl and extracted with ethyl acetate. The organic phase
was washed with water (20 mL) and brine (20 mL), and dried over
anhydrous Na2SO4. The crude product obtained was purified by PLC
(silica gel, 22% ethyl acetate in hexanes) to give (2R,5R,6R,50R)-ent-
11A as a pale yellow viscous liquid (0.285 g, 61% yield). 1H NMR
(2S,5S,6S,50S)-10A (0.118 g, 0.45 mmol) was treated with 90%
trifluoroacetic acid (7 mL) at 0 ꢂC. The mixture was slowly warmed
up to room temperature for 5 h. The solvents were freeze-dried
overnight to give a crude product, which was purified by pre-
parative thin layer chromatography (PLC, silica gel, 1% MeOH in
EtOAc) to give (ꢀ)-pentenomycin I (1) (54 mg, 83% yield) as an
amorphous powder (viscous liquid or syrup on standing). 1H NMR
(300 MHz, CDCl3): d 7.45–7.40 (m, 2H, ArH), 7.40–7.33 (m, 3H, ArH),
(300 MHz, D2O):
d
7.73 (dd, J¼4.4, 2.7 Hz, 1H, ]CHb), 6.32 (d,
6.65 (d, J¼3.1 Hz, 1H, CH]C), 4.42 (d, J¼3.1 Hz, 1H, CHOH), 4.27 (d,
J¼5.5 Hz, 1H, CHH), 3.44 (s, 3H, OCH3), 3.35 (d, J¼5.5 Hz, 1H, CHH),
3.26 (s, 3H, OCH3), 1.50 (br s, 1H, OH), 1.35 (s, 3H, CH3), 1.32 (s, 3H,
J¼4.4 Hz, 1H, ]CHa), 4.73 (s, 1H, CHOH), 3.72 (ABq, J¼11.8 Hz, 1H,
CHAHB–OH), 3.69 (ABq, J¼11.8 Hz, 1H, CHAHB–OH). 13C NMR
(75 MHz, D2O):
d
210.1 (C]O), 164.9 (CH), 133.7 (CH), 76.6 (C), 71.9
CH3). 13C NMR (75 MHz, CDCl3):
d 195.9 (C]O), 148.3 (CH), 143.6
(CH), 63.3 (CH2). IR (neat): nmax 3416 s, 1712 s, 1636 m, 1385 m, 1262
(C), 134.6 (2ꢃCH), 129.7 (2ꢃCH), 129.4 (CH), 128.8 (C), 99.6 (C), 98.1
(C), 82.2 (CH), 77.1 (C), 61.1 (CH2), 50.0 (CH3), 48.2 (CH3),17.74 (CH3),
17.71 (CH3). IR (neat): nmax 3427 m, 1731 s, 1558 w, 1384 m, 1124 s,
1043 s, 754 s cmꢀ1. MS: m/z (% relative intensity): 367 (Mþþ1, 0.5),
m, 1162 m, 1047 m cmꢀ1. MS: m/z (% relative intensity): 145 (Mþþ1,
29
12), 125 (100), 99 (70), 95 (56), 81 (77), 67 (71). [
a
]
ꢀ31.2 (c 1.50,
D
EtOH) (lit.5
[a
]
D ꢀ32.0 (c 0.3, EtOH)).
139 (56), 123 (56), 123 (100), 111 (68). HRMS (ESI-TOF) calcd for
29
4.17. (D)-Pentenomycin I (ent-1)
C18H22O6SNa: 389.1027; found: 389.1015. [
a]
ꢀ85.35 (c 1.14,
D
CHCl3).
(2R,5R,6R,50R)-ent-10A (0.135 g, 0.52 mmol) was treated with
90% trifluoroacetic acid (8 mL) at 0 ꢂC to room temperature for 5 h.
The solvents were freeze-dried overnight to give a crude product,
which was purified by PLC (silica gel, 2% MeOH in EtOAc) to give
[(þ)-pentenomycin I (ent-1) (61 mg, 82% yield) as an amorphous
powder (viscous liquid or syrup on standing). 1H NMR (300 MHz,
4.21. (D)-4,5-Dihydroxy-2-phenylsulfanyl-5-hydroxymethyl-
2-cyclopentenone (ent-12A)
(2R,5R,6R,50R)-ent-11A (0.122 g, 0.34 mmol) was stirred with
90% trifluoroacetic acid (4 mL) at 0 ꢂC. The mixture was slowly
warmed up to room temperature for 3.5 h. The solvent was freeze-
dried overnight to give a crude product, which was purified by PLC
(silica gel, 77% EtOAc in hexanes) to give ent-12A as colorless
crystals (67.2 g, 80% yield, mp 134–136 ꢂC). 1H NMR (300 MHz,
D2O):
d
7.73 (dd, J¼4.4, 2.7 Hz, 1H, ]CHb), 6.32 (d, J¼4.4 Hz, 1H,
]CHa), 4.73 (s, 1H, CHOH), 3.72 (ABq, J¼11.8 Hz, 1H, CHAHB–OH),
29
3.69 (ABq, J¼11.8 Hz, 1H, CHAHB–OH). [
(lit.9e
D þ30.0 (c 0.1, EtOH)).
a]
þ37.1 (c 0.28, EtOH)
D
[a]
acetone-d6):
d
7.61–7.44 (m, 5H, ArH), 6.71 (d, J¼2.8 Hz, 1H, ]CH),
4.18. (D)-Epipentenomycin I (ent-5)
4.57 (d, J¼2.8 Hz, 1H, CHOH), 3.83 (d, J¼11.6 Hz, 1H, CHH), 3.65 (d,
J¼11.6 Hz, 1H, CHH), 2.9 (br s, 3H OH). 13C NMR (75 MHz, CDCl3):
(2R,5R,6R,50S)-ent-10B (0.153 g, 0.59 mmol) was treated with
90% trifluoroacetic acid (9 mL) at 0 ꢂC to room temperature for 5 h.
The solvents were freeze-dried overnight to give a crude product,
which was purified by PLC (silica gel, 4% MeOH in EtOAc) to give
(þ)-epipentenomycin I (ent-5) (69 mg, 81% yield) as a colorless
d
200.7 (C]O), 147.9 (CH), 146.8 (C), 134.9 (2ꢃCH), 130.8 (2ꢃCH),
130.3 (CH), 102.0 (C), 78.6 (CH), 76.5 (C), 65.6 (CH2). IR (Nujol): nmax
3528 m, 1723 s, 1456 m, 1115 s, 1040 m, 769 s cmꢀ1. MS: m/z (%
relative intensity): 252 (Mþþ1, 45), 250 (34), 234 (100), 91 (31), 69
(34). HRMS (ESI-TOF) calcd for C12H12O4SNa: 275.0333; found:
29
viscous liquid. 1H NMR (300 MHz, D2O):
d
7.79 (dd, J¼6.1, 2.3 Hz,1H,
275.0346. [
a
]
þ81.8 (c 0.17, CHCl3).
D
]CHb), 6.47 (d, J¼6.1 Hz, 1H, ]CHa), 4.85–4.60 (m, 1H, CHOH), 3.84
29
(d, J¼12.0 Hz, 1H, CHH), 3.63 (d, J¼12.0 Hz, 1H, CHH). [
a]
þ68.9 (c
4.22. (2R,5R,6R,50R)-50-Hydroxy-20-oxo-30-iodospiro-
cyclopent-30-ene-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane
(ent-13A)
D
0.25, EtOH) (lit.7
[a]
D
þ130.0 (c 0.51, H2O)).
4.19. (L)-Epipentenomycin I (5)
A solution of (2R,5R,6R,50R)-ent-10A (0.625 g, 2.41 mmol), pyri-
dine (5 mL), and carbon tetrachloride (5 mL) was added to a solu-
tion of iodine (2.43 g, 9.64 mmol) in pyridine (5 mL) and carbon
tetrachloride (5 mL). After stirring for 1 h at room temperature in
the dark, the mixture was diluted with Et2O (3ꢃ15 mL) and washed
successively with water (20 mL), 1 M HCl (5 mL), saturated Na2S2O3
(20 mL), and brine (15 mL). The aqueous layer was extracted with
Et2O and the combined organic layers were dried over anhydrous
Na2SO4. After filtration and evaporation, the residue was purified by
column chromatography on silica gel (silica gel, 20% EtOAc in
hexanes) to give ent-13A as a white solid (0.901 g, 97% yield, mp
98–100 ꢂC), which was unstable on standing at room temperature.
(2S,5S,6S,50R)-10B (0.086 g, 0.33 mmol) was treated with 90%
trifluoroacetic acid (5 mL) at 0 ꢂC. The mixture was slowly warmed
up to room temperature for 5 h. The solvents were freeze-dried
overnight to give a crude product, which was purified by PLC (silica
gel, 1% MeOH in EtOAc) to give (ꢀ)-epipentenomycin I (5) (40 mg,
80% yield) as a colorless viscous liquid. 1H NMR (300 MHz, D2O):
d
7.79 (dd, J¼6.1, 2.3 Hz, 1H, ]CHb), 6.47 (d, J¼6.1 Hz, 1H, ]CHa),
4.85–4.60 (m, 1H, CHOH), 3.84 (d, J¼12.0 Hz, 1H, CHH), 3.63 (d,
J¼12.0 Hz, 1H, CHH). 13C NMR (75 MHz, D2O):
d 215.9 (C]O), 161.7
(CH), 135.6 (CH), 102.3 (C), 79.3 (CH), 65.0 (CH2). IR (neat): nmax
3449 s, 1722 m, 1638 s, 1259 m, 1106 s, 1044 m, 925 s cmꢀ1. MS: m/z
(% relative intensity): 145 (Mþþ1, 12), 135 (23), 121 (32), 113 (100),
1H NMR (300 MHz, CDCl3):
d
7.92 (d, J¼2.7 Hz, 1H, ]CH), 4.49 (d,
29
97 (46), 95 (53), 81 (57). [
a
]
ꢀ74.1 (c 0.20, EtOH) (lit.9f
[
a]
D ꢀ75.3
J¼2.7 Hz, 1H, CHOH), 4.24 (d, J¼11.2 Hz, 1H, CHH), 3.99–3.89 (br, 1H,
OH), 3.43 (s, 3H, OCH3), 3.37 (d, J¼11.2 Hz, 1H, CHH), 3.30 (s, 3H,
OCH3), 1.34 (s, 3H, CH3), 1.33 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
D
(c 1.15, MeOH)).
4.20. (2R,5R,6R,50R)-50-Hydroxy-20-oxo-30-phenylsulfanyl
spirocyclopentene-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane
(ent-11A)
d 198.0 (C]O), 166.4 (CH), 104.4 (C), 101.1 (C), 99.9 (C), 75.2 (CH),
74.7 (C), 63.1 (CH2), 48.7 (CH3), 48.1 (CH3), 18.68 (CH3), 18.60 (CH3).
IR (Nujol): nmax 3388 s, 1715 s, 1631 m, 1452 m, 1115 m, 1049
m cmꢀ1. MS: m/z (% relative intensity): 384 (Mþ, 0.27), 250 (45), 141
Trifluoroacetic anhydride (0.14 mL, 1.10 mmol) was added to
cooled (0 ꢂC) solution of (2R,5R,6R,50R)-ent-9A (0.258 g,
(41), 110 (100). HRMS (ESI-TOF) calcd for C12H17O6NaI: 406.9968;
29
a
found: 406.9969. [
a
]
D
ꢀ27.29 (c 0.98, CHCl3).

6322
M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
4.23. (2R,5R,6R,50R)-20-Oxo-30-phenylspirocyclopent-30-ene-
5,6-dimethoxy-5,6-dimethyl-[1,4]dioxane (ent-14A)
CHH), 3.90 (d, J¼10.71 Hz, 1H, CHH), 3.51 (s, 3H, OCH3), 3.44 (s, 3H,
OCH3), 1.44 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.33 (br s, 1H, OH). 13C
NMR (75 MHz, CDCl3):
d
198.9 (C]O), 159.5 (CH), 132.0 (2ꢃCH),
A round-bottomed flask was charged with phenylboronic acid
(46 mg, 0.38 mmol), (2R,5R,6R,50R)-ent-13A (96 mg, 0.249 mmol),
and PdCl2(PPh3)2 (10 mg, 0.012 mmol, 5 mol %). THF (1.5 mL) was
added followed by 2 M Na2CO3 (0.7 mL, 1.8 mmol). The resulting
reaction mixture was heated at 40 ꢂC under an argon atmosphere
overnight. The mixture was cooled to room temperature and ethyl
acetate (10 mL) was added followed by saturated NaHCO3 (20 mL)
and water (15 mL). The aqueous layer was extracted with EtOAc
(2ꢃ10 mL). The combined organic layers were washed with 0.5 N
NaOH (2ꢃ10 mL), brine (2ꢃ10 mL) and dried over anhydrous
Na2SO4. Filtration followed by evaporation gave the a crude prod-
uct, which was purified by column chromatography (silica gel, 25%
EtOAc in hexanes) to give (2R,5R,6R,50R)-ent-14A as a white solid
(58.5 g, 70% yield, mp 171–172 ꢂC). 1H NMR (300 MHz, CDCl3):
129.2 (CH), 128.9 (C), 128.3 (2ꢃCH), 121.9 (C), 109.79 (C), 100.74 (C),
97.5 (C), 81.6 (C), 78.6 (CH), 60.4 (CH2), 49.4 (CH3), 48.6 (CH3), 29.6
(CH), 18.9 (CH3), 18.7 (CH3). IR (neat) nmax 3497 s, 2221 m, 1732 s,
1615 m,1457 m, 1039 m, 755 m cmꢀ1. MS: m/z (% relative intensity):
358 (Mþ, 0.3), 336 (26), 220 (100), 149 (29), 93 (34), 73 (51). HRMS
29
(ESI-TOF) calcd for C20H22O6Na: 381.1409; found: 381.1442. [a]
D
ꢀ29.87 (c 0.23, CHCl3).
4.26. (2R,5R,6R,50R)-30-tert-Butylacetylenyl-50-hydroxy-
20-oxospirocyclopentene-5,6-dimethoxy-5,6-dimethyl-
[1,4]dioxane (ent-16Ab)
According to the general procedure D as described for ent-16Aa,
the reaction of (2R,5R,6R,50R)-ent-13A (173 mg, 0.450 mmol), tert-
butylacetylene (0.164 mL, 2.25 mmol), PdCl2(PPh3)2 (16 mg,
0.023 mmol, 5 mol %), CuI (9 mg, 0.045 mmol), and N,N-diisopro-
pylamine (0.19 mL, 1.35 mmol) provided a crude product, which
was purified by column chromatography (silica gel, 20% EtOAc in
hexanes) to give ent-16Ab as a white solid (152.8 mg, 90% yield,
d
7.80–7.75 (m, 2H, ArH), 7.71 (d, J¼2.1 Hz, 1H, ]CH), 7.38–7.30 (m,
3H, ArH), 4.87 (d, J¼2.1 Hz, 1H, CHOH), 3.89 (d, J¼11.1 Hz, 1H, CHH),
3.74 (d, J¼11.1 Hz, 1H, CHH), 3.43 (s, 3H, OCH3), 3.31 (s, 3H, OCH3),
1.47 (s, 3H, CH3), 1.35 (br s, 1H, OH), 1.34 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3):
d 198.6 (C]O), 153.4 (CH), 141.1 (C), 130.0 (C),
129.3 (CH), 128.5 (2ꢃCH), 127.1 (2ꢃCH), 99.5 (C), 98.0 (C), 83.2 (C),
76.3 (CH), 61.2 (CH2), 50.1 (CH3), 48.2 (CH3), 17.7 (2ꢃCH3). IR (neat):
nmax 3522 s, 1722 s, 1449 s, 1104 s, 1032 s, 997 s cmꢀ1. MS: m/z (%
relative intensity): 334 (Mþþ1, 1), 234 (54), 142 (24), 140 (100), 114
139–141 ꢂC). 1H NMR (300 MHz, CDCl3):
d
7.33 (d, J¼2.5 Hz, 1H,
]CH), 4.85 (d, J¼2.5 Hz, 1H, CHOH), 4.28 (d, J¼10.8 Hz, 1H, –CHH),
3.77 (d, J¼10.8 Hz, 1H, CHH), 3.42 (s, 3H, OCH3), 3.36 (s, 3H, OCH3),
1.60 (br s, 1H, OH), 1.35 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.23 (s, 3ꢃ3H,
(73). HRMS (ESI-TOF) calcd for C18H22O6Na: 357.1313; found:
CCH3). 13C NMR (75 MHz, CDCl3):
d 199.4 (C]O), 158.8 (CH), 129.3
29
387.1304. [
a
]
ꢀ290.7 (c 0.15, CHCl3).
(C), 107.5 (C), 100.7 (C), 81.6 (C), 78.5 (CH), 77.2 (C), 68.9 (C), 60.5
(CH2), 49.4 (CH3), 48.6 (CH2), 30.6 (3ꢃCH3), 28.1 (C), 18.9 (CH3), 18.8
(CH3). IR (film): nmax 3479 m, 2222 w, 1731 s, 1455 m, 1265 s, 1114 s,
1036 s cmꢀ1. MS: m/z (% relative intensity): 338 (Mþ, 0.6), 175 (100),
D
4.24. (D)-4,5-Dihydroxy-5-hydroxymethyl-2-phenyl-2-
cyclopentenone (ent-15A)
147 (33), 119 (24), 115 (47), 91 (60). HRMS (ESI-TOF) calcd for
29
(2R,5R,6R,50R)-ent-14A (50 mg, 0.176 mmol) was treated with
90% trifluoroacetic acid (1 mL) at 0 ꢂC. The mixture was slowly
warmed up to room temperature for 3.5 h. The solvent was freeze-
dried overnight to give a crude product, which was purified by PLC
(silica gel, 67% EtOAc in hexanes) to give ent-15A as a white solid
(27 mg, 90% yield, mp 127–130 ꢂC). 1H NMR (300 MHz, CDCl3):
C
18H26O6Na: 361.1619; found: 361.1629. [
a
]
D
ꢀ29.73 (c 0.4, CHCl3).
4.27. (D)-4,5-Dihydroxy-5-(hydroxymethyl)-2-
phenylacetylenyl-2-cyclopentenone (ent-17Aa)
(2R,5R,6R,50R)-ent-16Aa (86 mg, 0.238 mmol) was treated with
90% trifluoroacetic acid (1 mL) at 0 ꢂC. The mixture was slowly
warmed up to room temperature for 3.5 h. The solvent was freeze-
dried overnight to give a crude product, which was purified by PLC
(silica gel, 70% EtOAc in hexanes) to give ent-17Aa as a colorless
viscous liquid (45.5 mg, 90% yield). 1H NMR (300 MHz, acetone-d6):
d
7.73–7.71 (m, 3H, ArH and ]CH), 7.43–7.39 (m, 3H, ArH), 4.83 (d,
J¼2.6 Hz,1H, CHOH), 3.91 (d, J¼11.7 Hz,1H, CHH), 3.77 (d, J¼11.7 Hz,
1H, CHH), 2.40 (s, 3H, OH). 13C NMR (75 MHz, CDCl3):
202.7
d
(C]O), 151.8 (CH), 143.7 (C), 129.5 (C), 128.7 (CH), 128.0 (2ꢃCH),
127.3 (2ꢃCH), 101.4 (C), 76.5 (CH), 65.7 (CH2). IR (Nujol): nmax 3417
m, 1704 s, 1597 m, 1571 m, 1449 m, 1038 m, 759 s, 701 m cmꢀ1. MS:
m/z (% relative intensity): 221 (Mþ, 0.54), 189 (100), 115 (34), 91
d
7.65 (br s, 1H, ]CH), 7.61–7.50 (m, 2H, ArH), 7.40–7.28 (m, 3H,
ArH), 4.78 (br s, 1H, CHOH), 3.90–3.0 (m, 5H, CH2 and 3ꢃOH). 13
C
(57), 77 (13). HRMS (ESI-TOF) calcd for C12H12O4Na: 463.1360;
NMR (75 MHz, CDCl3): d 205.2 (C]O), 161.9 (CH), 131.7 (C), 131.5
29
found: 463.1347. [
a]
þ23.8 (c 0.31, EtOH).
(2ꢃCH), 129.4 (C), 129.1 (CH), 128.5 (2ꢃCH), 102.6 (C), 90.9 (C), 77.0
(CH), 74.7 (C), 64.5 (CH2). IR (film): nmax 3424 s, 3019 m, 2241 m,
1730 m, 1620 m cmꢀ1. MS: m/z (% relative intensity): 243 (Mþꢀ1,
D
4.25. (2R,5R,6R,50R)-50-Hydroxy-20-oxo-30-phenylacetylenyl
spirocyclopent-30-ene-5,6-dimethoxy-5,6-dimethyl-
[1,4]dioxane (ent-16Aa)
0.9), 125 (67), 78 (100). HRMS (ESI-TOF) calcd for C14H12O4Na:
29
267.0632; found: 267.0646. [
a]
þ16.0 (c 0.50, EtOH).
D
General procedure D: a mixture of (2R,5R,6R,50R)-ent-13A
(132 mg, 0.342 mmol), phenylacetylene (0.174 mL, 1.71 mmol),
PdCl2(PPh3)2 (12.3 mg, 0.015 mmol, 5 mol %), and CuI (8.6 mg,
0.034 mmol) was treated with N,N-diisopropylamine (0.14 mL,
1.026 mmol) at 0 ꢂC. The resulting yellow to dark-brown solution
was stirred at 0 ꢂC for 1 h. The mixture was partitioned with Et2O
and 1 M HCl. The aqueous layer was extracted with Et2O (3ꢃ20 mL).
The combined organic layers were washed with brine and dried
over anhydrous Na2SO4. Filtration and concentration gave the crude
reaction mixture, which was purified by column chromatography
(silica gel, 21% EtOAc in hexanes) to give ent-16Aa as a pale yellow
viscous liquid (88.8 mg, 72% yield). 1H NMR (300 MHz, CDCl3):
4.28. (D)-tert-2-Butylacetylenyl-4,5-dihydroxy-
5-(hydroxymethyl)-2-cyclopentenone (ent-17Ab)
(2R,5R,6R,50R)-ent-16Ab (69 mg, 0.292 mmol) was treated with
90% trifluoroacetic acid (1 mL) at 0 ꢂC. The crude product was pu-
rified by PLC (silica gel, 60% EtOAc in hexanes) to give (þ)-ent-17Ab
as a white solid (23.3 mg, 97% yield, mp 98–101 ꢂC). 1H NMR
(300 MHz, acetone-d6):
d
7.38 (d, J¼2.2 Hz, 1H, ]CH), 4.89 (br, 1H,
OH), 4.64 (br, 1H, CHOH), 4.50 (br, 1H, OH), 3.62 (br, 2H, CH2), 3.58
(br, 1H, OH), 3.05 (s, 3ꢃ3H, CH3). 13C NMR (75 MHz, CDCl3):
d 203.6
(C]O), 161.6 (CH), 129.9 (C), 106.6 (C), 81.6 (C), 77.8 (CH), 70.6 (C),
76.6 (C), 65.4 (CH2), 30.5 (3ꢃCH3). IR (Nujol): nmax 3418 s, 1714 s,
1633 s, 1465 m, 1050 s, 757 s cmꢀ1. MS: m/z (% relative intensity):
223 (Mþ, 2), 167 (31), 149 (100), 125 (26), 91 (51), 81 (29). HRMS
d
7.57 (d, J¼2.07 Hz,1H, ]CH), 7.61–7.50 (m, 2H, ArH), 7.34–7.30 (m,
3H, ArH), 5.00 (d, J¼2.07 Hz, 1H, CHOH), 4.25 (d, J¼10.71 Hz, 1H,

M. Pohmakotr et al. / Tetrahedron 64 (2008) 6315–6323
6323
29
manski, M.; Purcell, N.; Stoodley, R. J.; Palfreyman, M. N. J. Chem. Soc., Perkin
Trans. 1 1984, 2089–2096; (g) Verlaak, J. M. J.; Klunder, A. J. H.; Zwanenburg, B.
Tetrahedron Lett. 1982, 23, 5463–5466; (h) Phutdhawong, W.; Pyne, S. G.;
Baramee, A.; Buddhasukh, D.; Skelton, B. W.; White, A. H. Tetrahedron Lett.
2002, 43, 6047–6049; (i) Khan, F. A.; Rout, B. Tetrahedron Lett. 2006, 47,
5251–5253.
(ESI-TOF) calcd for C12H16O4Na: 247.0938; found: 247.0928. [a]
D
þ21.84 (c 0.2, CHCl3).
Acknowledgements
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We thank the Center for Innovation in Chemistry: the
Postgraduate EducationandResearchPrograminChemistry(PERCH-
CIC), the Thailand Research Fund (BRG4980005), and the Commis-
sion on Higher Education (CHE-RES-RG) for financial support.
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