Asymmetric synthesis and applications of chiral 3-phenylsulfinyl-3-sulfolenes

Article abstract of DOI:10.1016/S0040-4039(02)00883-3

The chiral 3-phenylsulfinyl-3-sulfolene 2 (S-form) was efficiently prepared in 92% ee by oxidation of sulfide 1 with Ti(O-i-Pr)₄/(-)-DET/t-BuOOH (1:4:1) in toluene. Thermal desulfonylation of 2 gave chiral diene 3. Deprotonation of 2 by BuLi followed by the reaction with alkyl halides gave regiospecifically the C-2 alkylated 3-sulfolenes 4-8. Intramolecular Diels-Alder reactions of compounds 7 and 8 gave the bicyclic products 9-11. Thermal desulfonylation of 4 generated chiral dienyl sulfoxide 15, which underwent thermal and Lewis acid-catalyzed Diels-Alder reactions with good regio-, stereo- and enantioselectivity.

Full text of DOI:10.1016/S0040-4039(02)00883-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4865–4870
Asymmetric synthesis and applications of chiral
3-phenylsulfinyl-3-sulfolenes
Shang-Shing P. Chou* and Pi-Wei Liang
Department of Chemistry, Fu Jen Catholic University, Taipei, Taiwan 242, Republic of China
Received 22 March 2002; revised 30 April 2002; accepted 2 May 2002
Abstract—The chiral 3-phenylsulfinyl-3-sulfolene 2 (S-form) was efficiently prepared in 92% ee by oxidation of sulfide 1 with
Ti(O-i-Pr)4/(−)-DET/t-BuOOH (1:4:1) in toluene. Thermal desulfonylation of 2 gave chiral diene 3. Deprotonation of 2 by BuLi
followed by the reaction with alkyl halides gave regiospecifically the C-2 alkylated 3-sulfolenes 4–8. Intramolecular Diels–Alder
reactions of compounds 7 and 8 gave the bicyclic products 9–11. Thermal desulfonylation of 4 generated chiral dienyl sulfoxide
15, which underwent thermal and Lewis acid-catalyzed Diels–Alder reactions with good regio-, stereo- and enantioselectivity.
© 2002 Elsevier Science Ltd. All rights reserved.
Chiral sulfoxides are valuable tools in organic synthe-
sis.1 The Diels–Alder reaction is also one of the most
useful methods in building various ring structures.2
Although chiral vinyl sulfoxides are versatile
dienophiles,3 chiral dienyl sulfoxides are less commonly
used in the Diels–Alder reaction,4 partly because of
their sensitivity to heat, light and acids.5 It is now well
established that 3-sulfolenes are useful precursors to
1,3-dienes.6 We have previously shown that 3-phenyl-
sulfinyl-3-sulfolene is a good precursor to the dienyl
sulfoxide, which can undergo many useful Diels–Alder
reactions.7 Herein we report an efficient synthesis of
chiral 3-phenylsulfinyl-3-sulfolenes and their synthetic
applications in inter- and intramolecular Diels–Alder
reactions.
Asymmetric oxidation of 3-phenylthio-3-sulfolene 1
could be carried out with chemical and enzymatic meth-
ods (Table 1). The ee values of product 2 were deter-
mined by HPLC using a chiral OD column with an
eluent mixture of Hex/EA/IPA=6:2:0.3. Preliminary
experiments showed that Sharpless oxidation8 was quite
efficient. With a fixed ratio of Ti(O-i-Pr)4/(−)-diethyl
tartrate (DET)/t-BuOOH=1:4:1, the best solvent
was found to be toluene (compare entries 1–5). Chang-
ing this ratio to 1:2:1 (entry 6), or adding 1 equiv. of
Table 1. Chiral oxidation of 3-phenylthio-3-sulfolene 2
Entry
Reagentsa
Solvent
Temp/time
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
A
A
A
A
A
B
C
D
E
THF
−20 to 0°C/12 h
−20 to 0°C/12 h
−20 to 0°C/12 h
−20 to 0°C/12 h
−20 to 0°C/12 h
−20 to 0°C/12 h
−20 to 0°C/24 h
−20 to 0°C/12 h
(1) 5°C/12 h
73
70
82
70
80
78
70
70
50
40
50
50
66
92
82
50
80
32
Dioxane
CH2Cl2
Xylene
Toluene
Toluene
Toluene
Toluene
EtOH
(2) 20°C/12 h
a (A) Ti(O-i-Pr)4/(−)-DET/t-BuOOH=1:4:1; (B) Ti(O-i-Pr)4/(−)-DET/t-BuOOH=1:2:1; (C) Ti(O-i-Pr)4/(−)-DET/t-BuOOH/H2O=1:4:1:1; (D)
Ti(O-i-Pr)4/(R,R)-diphenylethane-1,2-diol/t-BuOOH=1:4:1; (E) (1) pH 5.1 sodium acetate/O2/glucose oxidase from Aspergillus; (2) H2O2.
Keywords: asymmetric synthesis; chiral dienyl sulfoxides; 3-phenylsulfinyl-3-sulfolenes; Diels–Alder reactions.
* Corresponding author. Fax: 886 2 29041942; e-mail: chem1004@mails.fju.edu.tw
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00883-3

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S.-S. P. Chou, P.-W. Liang / Tetrahedron Letters 43 (2002) 4865–4870
water9 (entry 7) to the system lowered the enantioselec-
tivity. Using a chiral diol (entry 8) to replace (−)-DET
also decreased the ee. The enzymatic oxidation10 (entry
9) was less efficient. The highest ee value we obtained
for 2 was 92% (entry 5). After a single recrystallization
the pure S-form of chiral 3-phenylsulfinyl-3-sulfolene 2
was obtained, [h]2D4 +142.5 (c 1.0, CH2Cl2). The struc-
ture of 2 was proven by X-ray crystallography (Fig. 1).†
The vinyl proton of 2 appeared at l 6.8 ppm, signifi-
cantly more downfield than that of the sulfide 1 (l 5.8
ppm). Compound 2 was desulfonylated to the diene 3
(R-form), [h]2D4 +96.0 (c 1.0, CH2Cl2), in 82% yield by
refluxing in toluene for 3 h. In this reaction it is
essential to use sodium bicarbonate to quench the acid
generated, and to add some hydroquinone (HQ) to
prevent the free-radical initiated polymerization of
diene 3.
Treatment of a mixture of 3-sulfolene 2 and hexa-
methylphosphoric amide (HMPA, 4 equiv.) in THF with
BuLi/hexane (2.2 equiv.) at −105°C followed by the
addition of an alkyl halide (1 equiv.) gave regiospecifi-
Figure 1. X-Ray crystal structure of compound 2.
Table 2. Deprotonation of 3-sulfolene 2 and subsequent reaction with electrophiles
Entry
Alkyl halide
R
Product (S,S)/(S,R)a
Yield (%)
1
2
3
4
5
CH3I
CH2ꢀCHCH2Br
PhCH2Br
CH2ꢀCH(CH2)3I
CH2ꢀCH(CH2)4I
CH3
CH2ꢀCHCH2
PhCH2
CH2ꢀCH(CH2)3
CH2ꢀCH(CH2)4
4 (6:1)
5 (100:0)
6 (5:1)
7 (4:1)
8 (4:1)
88
84
75
80
82
a The diastereomeric ratios were determined by 1H NMR.
† Crystallographic data (excluding structure factors) for structures 2, 16, 17 and 20 in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers CCDC 181299, 181300, 181301 and 181454, respectively. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk; or www: http://www.ccdc.cam.ac.uk].

S.-S. P. Chou, P.-W. Liang / Tetrahedron Letters 43 (2002) 4865–4870
4867
cally the C-2 alkylated products 4–8 in good yields
(Table 2). The regiospecific alkylation can be explained
by first deprotonation at the most acidic C-5 position
followed by second deprotonation at C-2, as similar to
that observed for 3-phenylsulfonyl-3-sulfolene.11 The
reaction with allyl bromide (entry 2) yielded only one
enantiomer, whereas the reactions with other elec-
trophiles all gave a mixture of two diastereomers. The
stereoselective formation of the (S,S)-diastereomer for
compounds 4–8 seems to derive from a preferential
deprotonation of the pro-S hydrogen due to the steric
hindrance of the phenyl group. Although these
diastereomers could not be separated by column chro-
matography, both of these isomers could be converted
to the same diene by thermal desulfonylation.
could be assigned on the basis of the 13C NMR spectra.
The trans isomer has more downfield chemical shifts for
the aliphatic carbons at the ring junction than those of
the cis isomer.12 In contrast, the cyclization of 8 gave
only the trans stereoisomer 11, [h]2D4 +36.5 (c 1.0,
CH2Cl2). The ring junction stereochemistry of com-
pounds 9–11 was confirmed by m-CPBA oxidation to
the corresponding sulfones 12–14, which were identical
with the literature data.11 The stereoselectivity of these
IMDA reactions was similar to that observed for the
sulfone-substituted dienes.11
Thermal desulfonylation of 4 gave the diene 15, [h]D24
+280.2 (c 1.0, CH2Cl2), in 90% yield. Diene 15 was
found by NOE technique to have the Z configuration.
Although quite a few chiral 2-sulfinyl-1,3-butadienes
have been used to study the Diels–Alder reactions,13–17
chiral diene 15 has never been synthesized.18 Thus we
were interested in studying the Diels–Alder reactions of
diene 15 with some dienophiles in order to determine
the regio-, stereo- and enantioselectivity of these reac-
tions (Scheme 2), which were found to vary with the
reaction conditions (Table 3). Heating a solution of 15
Compounds 7 and 8 could be converted to the bicyclic
products 9–11 by heating in toluene at 200°C for 16 h
(Scheme 1). Presumably, the triene intermediates were
generated in situ, which then underwent intramolecular
Diels–Alder reactions to give the cyclized products.
Compound 7 yielded an inseparable mixture of trans/
cis products 9 and 10 (5:1). However, their structures
O
S
O
Ph
NaHCO3
S
Ph
(CH2)nCH=CH2
S
O2
pyr, HQ
200 0C, 16 h
(CH2)nCH=CH2
7, n = 3
8, n = 4
O
S
O
S
H Ph
SO2Ph
H
SO2Ph
H
Ph
H
m-CPBA
+
+
97%
H
H
H
H
13
10 74 % (5 : 1)
12, n = 1
14, n = 2
9, n = 1
11, n = 2 (70 %)
Scheme 1.
O
O
O
S
S
O
O
N
S
Ph
H
Ph
CH3
NaHCO3
Ph
Ph
CH3
CH3
H
S
H
HQ, toluene
, 3 h
O2
O
O
15
N
4
Ph
MeO2C
C C H
16
O
O
S
S
Ph
Ph
H
H
+
CH3
CH3
MeO2C
MeO2C
18
(major)
17
Scheme 2.

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S.-S. P. Chou, P.-W. Liang / Tetrahedron Letters 43 (2002) 4865–4870
Table 3. Diels–Alder reactions of diene 15 with dienophiles
Entry
Dienophilea
Reaction conditionb
Product
Yield (%)
1
2
3
4
5
6
N-Phenylmaleimide
N-Phenylmaleimide
N-Phenylmaleimide
HꢁCꢂCꢁCO2Me
HꢁCꢂCꢁCO2Me
HꢁCꢂCꢁCO2Me
Toluene, reflux, 24 h
CH2Cl2, rt, 36 h
ZnCl2, CH2Cl2, rt, 24 h
Toluene, reflux, 24 h
Toluene, 90°C, 24 h
ZnCl2, toluene, 75°C, 36 h
16
16
16
80
84
90
60
70
75
17+18 (4:1)
17+18 (7:1)
17
a The dienophile was used in 4 equiv.
b Small amount of hydroquinone (HQ) was present.
of HOMO (diene)–LUMO (dienophile) and thus mak-
ing this reaction more stereoselective.
and N-phenylmaleimide (4 equiv.) in toluene at reflux
gave the cycloaddition product 16, [h]2D4 +90.3 (c 1.0,
CH2Cl2), in 80% yield (entry 1). This reaction could
also be carried out in CH2Cl2 at room temperature
(entry 2) or in the presence of ZnCl2 (entry 3) to give
higher yields of 16. The reaction of diene 15 with
methyl propiolate (4 equiv.) in refluxing toluene (entry
4) gave a separable mixture of stereoisomers 17 and 18
(4:1). The ratio of the mixture changed to 7:1 if the
reaction was carried out at 90°C (entry 5). Further-
more, only product 17, [h]2D4 +150.2 (c 1.0, CH2Cl2), was
obtained when ZnCl2 was used as the catalyst (entry 6).
The structures of 16 and 17 were proven by X-ray
crystallography (Figs. 2 and 3).† The structure of 18,
[h]2D4 +86.0 (c 1.0, CH2Cl2), was proven by first m-
CPBA oxidation to the sulfone 19, [h]2D4 −72.0 (c 1.0,
CH2Cl2), which upon treatment with DDQ in CH2Cl2
gave the aromatized product 20 whose structure was
proven by X-ray crystallography (Fig. 4).†
In summary, we have efficiently synthesized the chiral
3-phenylsulfinyl-3-sulfolene 2, which can not only be
converted to the chiral diene 3, but also be regiospecifi-
cally alkylated to give substituted products 4–8. Com-
pounds 7 and 8 underwent intramolecular Diels–Alder
reactions to give bicyclic products 9–11. The inter-
molecular Diels–Alder reactions of diene 15 with
dienophiles gave the cyclized products 16–18 with good
The stereospecific formation of cycloaddition product
16 from diene 15 and N-phenylmaleimide can be ratio-
nalized as shown in Fig. 5. The chiral dienyl sulfoxide
15 prefers to adopt a conformation in which the SꢁO
bond is parallel to the CꢀC bond,13 and endo addition
of N-phenylmaleimide from the less hindered side of
the diene (below the plane) would give the observed
product 16. Since the Lewis acid-catalyzed reaction
gave the same product 16, it is assumed that similar
steric arrangements are involved. The formation of
products 17 and 18 from the thermal reaction of diene
15 with methyl propiolate indicates that the regioselec-
tivity of the cycloaddition is dominated by the phenyl-
sulfinyl group at C-2 over the methyl group at C-1.
Preferential approach of methyl propiolate from the
bottom face of the diene would give the major product
17 (Fig. 6). It is important to note that in the presence
of Lewis acid this reaction leads to only one stereoiso-
mer 17, presumably by lowering the energy difference
Figure 2. X-Ray crystal structure of compound 16.

S.-S. P. Chou, P.-W. Liang / Tetrahedron Letters 43 (2002) 4865–4870
4869
Figure 3. X-Ray crystal structure of compound 17.
O
S
CH3
H
C
Figure 4. X-Ray crystal structure of compound 20.
C
C
O
OCH3
Figure 6. Favorable approach of methyl propiolate with chi-
ral dienyl sulfoxide 15.
O
S
CH3
edged (NSC 90-2113-M-030-009). We also thank Mr.
Gene-Hsiang Lee at Instrumentation Center of
National Taiwan University for the measurement of
X-ray crystal structures.
O
N
O
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