A synthesis of (4S)-2-(acetoxymethyl)-4-(tert-butyl-diphenylsilyloxy)-2-cyclopenten-1-one

Article abstract of DOI:10.1016/S0957-4166(02)00145-3

We describe here a synthesis of (4S)-2-(acetoxymethyl)-4-(tert-butyldiphenylsilyloxy)-2-cyclopenten-1-one 1 from L-malic acid in seven steps via an intramolecular aldolization-dehydration cyclization reaction of the acyclic 1,6-dialdehyde 10. The conditio

Full text of DOI:10.1016/S0957-4166(02)00145-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 461–464
A synthesis of (4S)-2-(acetoxymethyl)-4-
(tert-butyl-diphenylsilyloxy)-2-cyclopenten-1-one
Xiao-Xin Shi,a,b,* Qing-Quan Wub and Xia Lua
aThe Faculty of Chemistry and Pharmaceutical Engineering, East China University of Science and Technology, PO Box 361,
130 Mei-Long Road, Shanghai 200237, PR China
bShanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Feng-Ling Road, Shanghai 200032, PR China
Received 30 July 2001; accepted 14 March 2002
Abstract—We describe here a synthesis of (4S)-2-(acetoxymethyl)-4-(tert-butyldiphenylsilyloxy)-2-cyclopenten-1-one 1 from
L
-malic acid in seven steps via an intramolecular aldolization–dehydration cyclization reaction of the acyclic 1,6-dialdehyde 10.
The conditions of the intramolecular aldolization–dehydration cyclization reaction were also optimized. © 2002 Published by
Elsevier Science Ltd.
L
-malic acid according to a known procedure.10 Com-
1. Introduction
pound 2 was treated with excess thionyl chloride to
produce an acyl chloride which was immediately
exposed to 6 equiv. of fresh Grignard reagent 3
(Scheme 2)11 in THF to give the ketodiester 4 in 75%
yield. With compound 4 in hand, we first tried Dieck-
mann cyclization in order to get a useful cyclic com-
pound 5, however, the reaction failed to give the
desired product 5, and only an elimination product 6
was observed. We then turned to protect the carbonyl
group of 4 with 1.2 equiv. of 1,3-propanedithiol and 1.5
equiv. of boron trifluoride etherate to afford the dithi-
ane 7 in 85% yield. Methanolysis of compound 7 in the
presence of catalytic K2CO3 gave 8, the temperature
here should be kept at around −5°C in order to avoid
marked racemization. Without purification, the crude
compound 8 was directly treated with 2 equiv. of
tert-butylchlorodiphenylsilane and 4 equiv. of imida-
zole to yield silyl ether 9 in 84% yield from 7. It was
observed that hydroxy diester 8 underwent gradual
lactonization and polymerization. So immediate use of
the crude 8 was imperative. Reduction of compound 9
with 3 equiv. of DIBAL-H at −78°C produced dialde-
hyde 10 which underwent an intramolecular aldoliza-
tion–dehydration cyclization reaction to give the cyclic
enal 11 in a moderate yield. The dialdehyde 10 could
not be purified and stored due to polymerization. But,
it was stable enough in dilute solution to be further
used to perform the intramolecular aldolization–dehy-
dration cyclization reaction. The yield of this cycliza-
tion reaction depended on the concentration of the
Both racemic and enantiomerically pure 4-hydroxy-2-
(hydroxymethyl)-2-cyclopenten-1-one are versatile syn-
thetic intermediates in the syntheses of a number of
cyclopentanoid natural products.1–5 The racemic 4-
hydroxy-2-(hydroxymethyl)-2-cyclopenten-1-one
was
synthesized from 2-methyl-3-(hydroxymethyl)furan.6
The (4R)-enantiomer of the compound and its deriva-
tives were synthesized from (−)-quinic acid.7–9 Recently,
the (4S)-enantiomer of the compound and its deriva-
tives became valuable to us because of their use in the
total syntheses of prostanoid natural products. But, to
the best of our knowledge, synthesis of the (4S)-enan-
tiomer of the compound has not been reported in the
literature. Now we would like to report a synthesis of
(4S)-2-(acetoxymethyl)-4-(tert-butyldiphenylsilyloxy)-2-
cyclopenten-1-one 1 namely a protected form of (4S)-4-
hydroxy-2-(hydroxymethyl)-2-cyclopenten-1-one.
2. Results and discussion
As outlined in Scheme 1, the title compound 1 was
synthesized in six steps starting from compound 2,
which is readily available by a one-pot reaction with
* Corresponding author. Fax: (8621)64252485; e-mail: xxshi@
ecust.edu.cn
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00145-3

462
X.-X. Shi et al. / Tetrahedron: Asymmetry 13 (2002) 461–464
catalysts, almost no racemization was observed, but
these amines only gave low yields. Fortunately, ammo-
nium salts turned to be good catalyses. Thus, ammo-
nium salts such as pyrrolidinium acetate and
pyridinium p-toluenesulfonate gave acceptable yields
and excellent ee values. Toluene and dichloromethane
were suitable solvents. Reduction of enal compound 11
with sodium cyanoborohydride gave the allyl alchol 12.
Protection of the hydroxy group of 12 with excess
acetic anhydride then afforded the allyl ether 13 in 76%
yield from 11 and removal of the dithiane group of 13
with 3 equiv. of periodic acid12–14 produced the desired
cyclic enone 1 in 69% yield. It was confirmed that the
enantiomeric purity of the final compound 1 is >98% by
HPLC analysis on a chiralcel OD column.
In summary, the work described in this article provides
an approach to the useful chiron 1. The title compound
1 can be obtained from
L-malic acid in around 17%
overall yield from this seven-step synthesis. The reac-
tion conditions of the intramolecular aldolization–dehy-
dration cyclization were also optimized. It is worth
pointing out that the enal 11 could also be a useful
synthon for total syntheses of prostanoid compounds.
Scheme 1. (a) SOCl2 (excess), 40°C, 3 h then 6 equiv. of 3, in
THF, rt, 12 h; (b) 1,3-propanedithiol (1.2 equiv.), BF3·OEt2
(1.5 equiv.) CH2Cl2, −10°C, 4 h; (c) cat. K2CO3, in methanol,
−5°C, 5 h; then 2 equiv. of tert-butylchlorodiphenylsilane, 4
equiv. of imidazole, in CH2Cl2, rt, overnight; (d) DIBAL-H (3
equiv.), CH2Cl2, −78°C, 0.5 h; then cat. PPTS, toluene, 0°C,
18 h; (e) NaBH3CN (1.5 equiv.), methanol, rt 2 h; (f) Ac2O
(excess), triethylamine (3 equiv.), rt, overnight; (g) H5IO6 (3
equiv. of), THF, 10°C, 3 min.
3. Experimental
3.1. General methods
NMR spectra were acquired on Bruker AM-300 in
CDCl3 using TMS as internal standard. Proton and
carbon chemical shifts are reported on the delta scale as
parts per million (ppm). Mass spectra were recorded on
Finnigan 4021. IR spectra were recorded on Schimadzu
IR-400. In particular, methylene chloride was distilled
over CaH2. THF was distilled from sodium prior to
use. All chemicals were analytically pure and were used
as received without purification. Compound 2 was pre-
pared according to a known procedure.10
3.2. (2S)-Dimethyl-2-acetoxy-4-oxoadipate 4
Compound 2 (4.2 g, 22.1 mmol) was dissolved in
thionyl chloride (15 mL). The solution was warmed to
40°C and stirred for 3 h. Excess thionyl chloride was
removed by distillation in a vacuum with a dry ice trap.
Residue was immediately used as such without
purification.
To a rapidly stirred suspension of magnesium turning
(3.22 g, 132.5 mmol) in anhydrous THF (100 mL) were
added 1,2-dibromoethane (1.87 g, 10.0 mmol) and 2-
bromopropane (16.6 g, 135.0 mmol). Warming was
continued until magnesium disappeared. Then the solu-
tion was diluted with THF (250 mL) and cooled to
room temperature. A solution of monomethyl malonate
(7.83 g, 66.3 mmol) in THF (20 mL) was dropwise
added within 10 min. After addition, the temperature
was maintained at 45°C for 1.5 h then cooled down to
room temperature. The above fresh acyl chloride was
added and stirring was continued overnight. THF was
removed on a rotavapor, and the residue was dissolved
Scheme 2.
dialdehyde solution, solvents, temperature and cataly-
ses. Optimization of the reaction conditions was carried
out in order to avoid racemization and to get the best
yield. A catalyst was necessary for the intramolecular
aldolization–dehydration cyclization. As shown in
Table 1, bases and strong acids were poor catalysts for
the reaction: when strong acids such as HCl and p-
toluenesulfonic acid were used as catalysts, obvious
racemization occurred during the reaction. When
amines such as triethylamine and pyridine were used as

X.-X. Shi et al. / Tetrahedron: Asymmetry 13 (2002) 461–464
Table 1. Intramolecular aldolization–dehydration cyclization of 10
463
Entry
Solvent
Catalysis
Temp. (°C)
Time (h)
Yield (%)
Ee (%)a
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
DCMe
HCl
Et3N
Py
Rt
Rt
Rt
Rt
Rt
Rt
0
Rt
0
0
8
10
10
12
12
12
18
12
18
18
15
21
24
18
58
66
68
61
65
32
85
98
98
87
98
98
98
98
98
–
PTSb
PDAc
PPTSd
PPTS
PPTS
PPTS
PPTS
9
10
THF
a The ee value was determined by HPLC with Chiral OD column.
b p-Toluenesulfonic acid.
c Pyrrolidinium acetate.
d Pyridinium p-toluenesulfonate.
e Dichloromethane.
3.4. (2S)-Dimethyl-2-(tert-butyldiphenylsilyloxy)-4,4-
in a cooled 1N aqueous HCl (150 mL) solution. The
aqueous solution was extracted twice by ethyl acetate
(2×150 mL). Combined extracts was washed succes-
sively with water (50 mL) and brine (50 mL) and then
dried over anhydrous Na2SO4. Removal of the solvent
gave a crude oil, which was purified by chromatogra-
phy on silica gel to give (2S)-dimethyl-2-acetoxy-4-
(propylenedithio)adipate 9
To a stirred and cooled solution of compound 7 (3.03 g,
9.0 mmol) in anhydrous methanol (30 mL), added was
catalytic K2CO3 (124 mg, 0.9 mmol). The temperature
of the mixture was maintained around –5°C with a
ice-salt bath. The reaction was continued and moni-
tored by TLC. After compound 7 disappeared as shown
by TLC, solvent was immediately removed by a rotava-
por. The residue was dissolved in CH2Cl2 (30 mL),
tert-butylchlorodiphenylsilane (4.95 g, 18.0 mmol) and
imidazole (2.45 g, 36.0 mmol) were added. The solution
was stirred overnight, and then the reaction was
quenched by 1N HCl (30 mL) aqueous solution.
Organic layer was separated and aqueous layer was
extracted once more with CH2Cl2 (30 mL). Extracts
were combined and dried over anhydrous MgSO4.
Removal of solvent gave a crude oil which was purified
by chromatography to produce (2S)-dimethyl-2-(tert-
1
oxoadipate 4 (4.1 g, 16.7 mmol, 75%). H NMR l 2.12
(s, 3H), 3.14 (d, J=6.0 Hz, 2H), 3.52 (s, 2H), 3.757 (s,
3H), 3.763 (s, 3H), 5.51 (t, J=6.0 Hz, 1H). 13C NMR l
197.69, 169.80, 169.61, 166.93, 67.24, 52.64, 52.45,
49.06, 43.41, 20.45. MS (m/z) 248 (M++2). IR (neat)
2957, 1747 (br), 1231 (br) cm−1.
3.3. (2S)-Dimethyl-2-acetoxy-4,4-(propylenedithio)-
adipate 7
A solution of compound 4 (2.95 g, 12.0 mmol) in
CH2Cl2 (20 mL) was cooled to −10°C, 1,3-
propanedithiol (1.55 g, 14.3 mmol) and BF3·OEt2 (2.55
g, 18.0 mmol) were added in turn. The mixture was
stirred at −10°C for about 4 h, and the reaction was
monitored by TLC. After the reaction was complete, it
was quenched at once with saturated aqueous NaHCO3
solution (50 mL). The organic layer was separated, and
aqueous layer was extracted twice with CH2Cl2 (2×30
mL). The extracts were combined and dried over anhy-
drous MgSO4. Removal of the solvent gave a crude
product which was purified by chromatography to
afford (2S)-dimethyl-2-acetoxy-4,4-(propylenedithio)-
adipate 7 (3.42 g, 10.2 mmol, 85%). [h]D −158 (c 0.5,
butyldiphenylsilyloxy)-4,4-(propylenedithio)adipate
9
1
(3.73 g, 7.0 mmol, 78%). [h]D −226 (c 0.6, CH2Cl2). H
NMR l 1.07 (s, 9H), 1.88–1.95 (m, 2H), 2.71 (dd,
J=5.5 Hz; 14.9 Hz, 1H), 2.76–2.82 (m, 4H), 2.83 (dd,
J=5.9 Hz; 14.9 Hz, 1H), 3.02 (d, J=15.1 Hz, 1H), 3.07
(d, J=15.1 Hz, 1H), 3.26 (s, 3H), 3.62 (s, 3H), 4.62 (t,
J=5.9 Hz, 1H), 7.33–7.45 (m, 6H), 7.66–7.71 (m, 4H).
13C NMR l 172.73, 168.95, 135.90, 133.09, 132.86,
129.71, 129.59, 127.49, 127.34, 71.09, 51.56, 51.37,
47.98, 43.58, 43.03, 26.88, 26.40, 24.27, 19.31. MS (m/z)
502 (M+−OMe). IR (neat) 2951 (br), 1741 (br), 1429,
1113, 703, 508 cm−1. Anal. calcd for C27H36O5S2Si: C,
60.87; H, 6.81. Found: C, 60.98; H, 6.90%.
1
CH2Cl2). H NMR l 1.90–2.00 (m, 2H), 2.13 (s, 3H),
3.5. (9S)-9-(tert-Butyldiphenylsilyloxy)-7-formyl-1,5-
dithiaspiro[5,4]dec-7-ene 11
2.75 (d, J=4.7 Hz, 1H), 2.76 (d, J=6.8 Hz, 1H),
2.81–2.93 (m, 4H), 3.03 (s, 2H), 3.72 (s, 3H), 3.77 (s,
3H), 5.47 (dd, J=4.7 Hz; 6.7 Hz, 1H). 13C NMR l
170.32, 170.04, 168.90, 69.80, 52.63, 51.78, 48.57, 43.72,
39.17, 26.50, 26.30, 24.32, 20.80. MS (m/z) 336 (M+).
IR (neat) 2960, 1766, 1739, 1376, 1225 cm−1. Anal.
calcd for C13H20O6S2: C, 46.41; H, 5.99. Found: C,
46.31; H, 5.92%.
A solution of compound 9 (3.08 g, 5.78 mmol) in
CH2Cl2 (60 mL) was cooled to −78°C, 1 M DIBAL-H
solution (17.5 mL) in hexanes was added slowly within
5 min, then the solution was stirred at −78°C for 0.5 h.
The reaction was quenched with methanol (2 mL), and
the temperature was allowed to rise to 0°C. Aqueous

464
X.-X. Shi et al. / Tetrahedron: Asymmetry 13 (2002) 461–464
2N HCl solution (20 mL) was added, the organic layer
was separated and dried with anhydrous Na2SO4.
Removal of solvent by a rotavapor gave crude dialde-
hyde 10 which cannot be stored without decomposition
and should be immediately dissolved in toluene (60
mL). The catalyst (1.2 mmol) indicated in Table 1 was
added, and the solution was stirred overnight. The
organic phase was washed in turn with water (10 mL)
and brine (10 mL). After drying over anhydrous
MgSO4, the solvent was removed to produce a residue
which was purified by flash chromatography on silica
gel to afford (9S)-9-(tert-butyldiphenylsilyloxy)-7-for-
myl-1,5-dithiaspiro[5,4]dec-7-ene 11 in the yield as
fresh solution of H5IO6 (1.25 g, 5.48 mmol) in anhy-
drous THF (5 mL). After addition, stirring was contin-
ued at 10°C for 3 min. Then ethyl acetate (60 mL) and
water (20 mL) was immediately added. Organic layer
was separated and washed with saturated aqueous solu-
tion (15 mL) of Na2SO3 and brine (10 mL). The extract
was dried over anhydrous MgSO4. Removal of solvents
gave a crude product, which was purified by flash
chromatography on silica gel to afford the desired
cyclic enone (4S)-2-(acetoxymethyl)-4-(tert-butyldi-
phenylsilyloxy)-2-cyclopenten-1-one 1 (513 mg, 1.26
1
mmol, 69%). [h]D –67 (c 0.8, CH2Cl2). H NMR (C6D6)
l 1.07 (s, 9H), 1.59 (s, 3H), 2.15–2.32 (m, 2H), 4.41–
4.52 (m, 1H), 4.63 (d, J=15.5 Hz, 1H), 4.69 (d, J=15.4
Hz, 1H), 6.92 (d, J=2 Hz, 1H), 7.13–7.25 (m, 6H),
7.55–7.70 (m, 4H). MS (m/z) 409 (M++1). IR (neat)
2987, 1749, 1702, 1418, 1212, 736 cm−1. Anal. calcd for
C24H28O4Si: C, 70.55; H, 6.91. Found: C, 70.31; H,
6.88%.
1
shown in Table 1. [h]D −112 (c 1.0, CH2Cl2). H NMR
l 1.12 (s, 9H), 1.49–1.56 (m, 2H), 2.24–2.40 (m, 2H),
2.62 (dd, J=5.8 Hz; 13.7 Hz, 1H), 2.75–2.85 (m, 1H),
2.87 (dd, J=6.9 Hz; 13.7 Hz, 1H), 3.08–3.18 (m, 1H),
4.97–5.02 (m, 1H), 6.29 (d, J=2 Hz, 1H), 7.16–7.26 (m,
6H), 7.66–7.73 (m, 4H), 9.54 (s, 1H). 13C NMR l
188.10, 148.92, 135.83, 135.79, 133.54, 133.46, 130.06,
128.11, 127.96, 127.79, 127.47, 74.76, 54.23, 28.31,
27.96, 26.77, 23.76, 19.04.
Acknowledgements
3.6. (9S)-7-(Acetoxymethyl)-9-(tert-butyldiphenylsilyl-
oxy)-1,5-dithiaspiro[5,4]dec-7-ene 13
We thank the Chinese National Natural Science Foun-
dation (No. A-20172015) for the financial support of
this work.
To a solution of compound 11 (1.81 g, 3.98 mmol) in
methanol (10 mL) was added NaBH.3CN (375 mg, 5.96
mmol). After the reaction was complete, water (50 mL)
was added. The aqueous solution was extracted with
ethyl acetate (2×30 mL). The extracts were combined
and dried over anhydrous Na2SO4. Removal of the
solvent gave a crude oil. Acetic anhydride (6 mL) and
triethylamine (1.21 g, 12.0 mmol) were added. The
mixture was stirred overnight. The reaction was
quenched by water (30 mL), then the aqueous solution
was twice extracted with hexanes (2×30 mL). Extracts
were combined and dried over anhydrous Na2SO4.
Evaporation of solvent gave a residue which was chro-
matographed to afford (9S)-7-(acetoxymethyl)-9-(tert-
butyldiphenylsilyloxy)-1,5-dithiaspiro[5,4]dec-7-ene 13
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1
(1.51 g, 3.03 mmol, 76%). [h]D –92 (c 1.1, CH2Cl2). H
NMR l 1.07 (s, 9H), 1.75–1.92 (m, 1H), 2.00–2.10 (m,
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To a well stirred solution of compound 13 (910 mg,
1.82 mmol) in anhydrous THF (5 mL) was added a