C2-symmetric bis-sulfoxide: A novel chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols

Article abstract of DOI:10.1021/jo9919409

A new heterocyclic compound, C₂-symmetric bis-sulfoxide 1, has been found to be an efficient chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal fission. Both (R,R)- and (S,S)-1 are readily synthesized with high optical purity via asymmetric oxidation of 1,5-benzodithiepan-3-one (2). After acetalization of meso-1,2- diols 6a-e and a mono-TMS ether 6f with this chiral auxiliary 1, the resulting acetals 7a-f were subjected to base-promoted acetal fission upon treatment with potassium hexamethyldisilazide (KHMDS) followed by acetylation or benzylation to give the desymmetrized diol derivatives 8a-f with high diastereoselectivity. The chiral auxiliary 1 is readily removed by acid- promoted hydrolysis and can be recovered without a loss in enantiomeric excess.

Full text of DOI:10.1021/jo9919409

3284
J . Org. Chem. 2000, 65, 3284-3291
C2-Sym m etr ic Bis-su lfoxid e: A Novel Ch ir a l Au xilia r y for
Asym m etr ic Desym m etr iza tion of Cyclic m eso-1,2-Diols
Naoyoshi Maezaki,† Atsunobu Sakamoto,† Noboru Nagahashi,† Motohiro Soejima,†
Ying-Xia Li,† Tsuneaki Imamura,† Naoto Kojima,† Hirofumi Ohishi,‡ Ken-ichi Sakaguchi,§
Chuzo Iwata,† and Tetsuaki Tanaka*,†
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita,
Osaka 565-0871, J apan, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki,
Osaka 569-1094, J apan, and Research Center for Protein Engineering, Institute for Protein Research,
Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, J apan
Received December 20, 1999
A new heterocyclic compound, C2-symmetric bis-sulfoxide 1, has been found to be an efficient chiral
auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal
fission. Both (R,R)- and (S,S)-1 are readily synthesized with high optical purity via asymmetric
oxidation of 1,5-benzodithiepan-3-one (2). After acetalization of meso-1,2-diols 6a -e and a mono-
TMS ether 6f with this chiral auxiliary 1, the resulting acetals 7a -f were subjected to base-promoted
acetal fission upon treatment with potassium hexamethyldisilazide (KHMDS) followed by acetylation
or benzylation to give the desymmetrized diol derivatives 8a -f with high diastereoselectivity. The
chiral auxiliary 1 is readily removed by acid-promoted hydrolysis and can be recovered without a
loss in enantiomeric excess.
Sch em e 1
In tr od u ction
Asymmetric desymmetrization of compounds with a
σ-symmetric plane is an important transformation for
synthesizing versatile chiral building blocks for various
natural products. This area of chemistry has been
extensively investigated in an effort to develop efficient
methods.1 Recently, we reported a novel asymmetric
desymmetrization of σ-symmetric diols based on the base-
promoted diastereoselective acetal fission of R-sulfinyl
acetals using a new chiral auxiliary, 1, with C2-symmetry
as shown in Scheme 1.2 This methodology was success-
fully applied to a synthesis of (-)-allosamizoline3 and (-)-
gala-quercitol.4 One of the advantages of this chiral
auxiliary is that acetalization of meso-diols gives only one
product (step A), whereas production of more than one
product is an inevitable problem with chiral auxiliaries
lacking symmetry. In addition, no regio- and geometric
isomers of the enol ether are formed in the acetal
cleavage reaction (step B), thereby making the whole
process simple. To the best of our knowledge, this is the
first use of a C2-symmetric chiral auxiliary for the
asymmetrization of σ-symmetric diols.5 In addition, this
methodology constitutes a conceptually novel application
of an R-sulfinyl carbanion for asymmetric reaction.6
In this paper, we report the full details of the synthesis
of the C2-symmetric bis-sulfoxide 1 and its application
to asymmetric desymmetrization of cyclic meso-1,2-diols.
Resu lts a n d Discu ssion
Syn t h esis of C2-Sym m et r ic Bis-su lfoxid e a n d
Str u ctu r a l Deter m in a tion . As shown in Schemes 2 and
3, the standard samples of optically pure (R,R)- and
(S,S)-1 were synthesized via optical resolution using
diethyl tartrate as a chiral auxiliary. 1,2-Benzenedithiol7
was condensed with 1,3-dichloroacetone in the presence
of DMAP to give 2 in 76% yield. After the ketone 2 was
acetalized with the bis-trimethylsilyl ether of (+)-diethyl
tartrate by Noyori’s method,8 one of the sulfide moieties
(5) (a) Harada, T. Hayashiya, T.; Wada, I.; Oku, A. J . Am. Chem.
Soc. 1987, 109, 527-532. Harada, T.; Hayashiya, T.; Wada, I.; Oku,
A. J . Org. Chem. 1989, 54, 2599-2605. Harada, T.; Oku, A. Synlett
1994, 95-104. Kinugasa, M.; Harada, T.; Oku, A. J . Am. Chem. Soc.
1997, 119, 9067-9068. Kinugasa, M.; Harada, T.; Oku, A. Tetrahedron
Lett. 1998, 39, 4529-4532. (b) Suemune, H.; Watanabe, K.; Kato, K.;
Sakai, K. Tetrahedron: Asymmetry 1993, 4, 1767-1770. Sakai, K.;
Suemune, H. Tetrahedron: Asymmetry 1993, 4, 2109-2118. (c)
Fujioka, H.; Nagatomi, Y.; Kitagawa, H.; Kita, Y. J . Am. Chem. Soc.
1997, 119, 12016-12017. Fujioka, H.; Nagatomi, Y.; Kotoku, N.;
Kitagawa, H.; Kita, Y. Tetrahedron Lett. 1998, 39, 7309-7312.
(6) Ogura, K. Comprehensive Organic Synthesis; Trost B. M.,
Fleming I., Schreiber, S. L., Eds.; Pergamon Press: New York, 1991;
Vol. 1, Chapter 2.3, pp 505-539. Krief, A. Comprehensive Organic
Synthesis; Trost B. M., Fleming I., Pattenden, G., Eds.; Pergamon
Press: New York, 1991; Vol. 3, Chapter 1.3, pp 85-191. Walker A. J .
Tetrahedron: Asymmetry 1992, 3, 961-998. Carreno, M. C. Chem. Rev.
1995, 95, 1717-1760.
† Graduate School of Pharmaceutical Sciences, Osaka University.
‡ Osaka University of Pharmaceutical Sciences.
§ Institute for Protein Research, Osaka University.
(1) Reviews for chemical asymmetric desymmetrization: Ward, R.
S. Chem. Soc. Rev. 1990, 19, 1-19. Maier M. Organic Synthesis
Highlights II; Waldmann H., Ed.; VHC: New York, 1995; pp 203-
222. Willis, M. C. J . Chem. Soc., Perkin Trans. 1 1999, 1765-1784.
(2) Maezaki, N.; Sakamoto, A.; Soejima, M.; Sakamoto, I.; Li, Y. X.;
Tanaka, T.; Ohishi, H.; Sakaguchi, K.; Iwata, C. Tetrahedron: Asym-
metry 1996, 7, 2787-2790.
(3) Maezaki, N.; Sakamoto, A.; Tanaka, T.; Iwata, C. Tetrahedron:
Asymmetry 1998, 9, 179-182.
(4) Maezaki, N.; Nagahashi, N.; Yoshigami, R.; Iwata, C.; Tanaka,
T. Tetrahedron Lett. 1999, 40, 3781-3784.
(7) Giolando, D. M.; Kirschbaum, K. Synthesis 1992, 451-452.
(8) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357-1358.
10.1021/jo9919409 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000

C2-Symmetric Bis-sulfoxide
J . Org. Chem., Vol. 65, No. 11, 2000 3285
F igu r e 1. ORTEP drawing of 4a .
F igu r e 2. ORTEP drawing of (R,R)-1.
Sch em e 2
F igu r e 3. Conformational energies of mono-sulfoxide 5 and
plausible mechanism of diastereoselective oxidation.
various oxidation conditions of racemic 5 were examined,
the undesirable meso-1 was a major product, e.g., m-
CPBA [(()-1:meso ) 1:2], dimethyldioxirane (1:2),10 H2O2/
SeO2 (meso only).11 Only ozone oxidation (dry ozonation)12
provided mainly (()-1 (3:1); thus bis-sulfoxides (R,R)- and
(S,S)-1 were obtained as the main products from (R)- and
(S)-5, respectively.13 The X-ray single-crystal structural
analysis of (R,R)-1 revealed its absolute configuration and
boat conformation of the seven-membered ring (Figure
2).9 The bis-sulfoxide 1 is a stable crystal and can be
stored for at least 1 month at room temperature without
loss of its chemical and optical purities (Scheme 3).
The reversed selectivity observed in ozone oxidation
of the mono-sulfoxide 5 is rationalized as follows. The
conformational equilibrium between the two conformers
A and B would lie preferentially to conformer A, since
the axial lone pair of the sulfide moiety in conformer B
suffers from unfavorable dipole-dipole interaction with
the axial sulfoxide, as shown in Figure 3. Conformational
analysis using the MOPAC program (AM114 and PM315
methods) supported this speculation. The heat of forma-
tion of A is about 6 kcal/mol more stable than that of B.
In the conformer A, the sulfide’s nucleophilic attack on
the bulky oxidants would proceed at the equatorial lone
Sch em e 3
in 3 was oxidized to sulfoxide with 1 equiv of m-CPBA
to give the separable diastereomeric isomers 4a and 4b.
The absolute configuration of 4a was unambiguously
determined as the R configuration by single-crystal X-ray
analysis (Figure 1).9 Thus, the absolute configuration at
the sulfoxide was established as R in 4a .
Acid-promoted hydrolysis of the acetal 4a (p-TsOH‚H2O
or H2SO4 in THF-water) was not successful in that it
gave many unidentified products, whereas base-promoted
deacetalization of 4a with KHMDS proceeded smoothly
to give the ketosulfoxide (R)-5 in 83% yield. Although
(10) Murray, R. W.; J eyaraman, R.; Pillay, M. K. J . Org. Chem. 1987,
52, 746-748.
(11) Drabowicz, J .; Mikolajczyk, M. Synthesis 1978, 758-759.
(12) Cohen, Z.; Keinan, E.; Mazur, Y.; Varkony, T. H. J . Org. Chem.
1975, 40, 2141-2142. Keinane, E.; Mazur, Y. Synthesis 1976, 523-
524.
(13) A similar reversal of selectivities between ozone and m-CPBA
has been reported previously, see: Aggarwal, V. K.; Davies, I. W.;
Franklin, R.; Maddock, J .; Mahon, M. F.; Molloy, K. C. J . Chem. Soc.,
Perkin Trans. 1 1994, 2363-2368.
(14) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902-3909.
(15) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220.
(9) Friedel pair reflections and anomalous scatterings were used to
determine the absolute configuration.

3286 J . Org. Chem., Vol. 65, No. 11, 2000
Ta ble 1. Asym m etr ic Oxid a tion of 1,5-Ben zod ith iep a n e-3-on e (2)
Maezaki et al.
entry
conditions (equiv)
Davis’ reagent (1.0)
TBHP (1.1), Ti(O-i-Pr)4 (1.0), (+)-DET (2.0), H2O (1.0)
TBHP (1.0), Ti(O-i-Pr)4 (1.0), (+)-DET (2.0)
TBHP (2.0), Ti(O-i-Pr)4 (1.0), (+)-DET (4.0)
CHP (1.1), Ti(O-i-Pr)4 (1.0), (+)-DET (2.0)
CHP (2.0), Ti(O-i-Pr)4 (1.0), (+)-DET (4.0)
time (days)
yielda (%)
eeb (%)
confign
1
2
3
4
5
6
3
7
7
2
7
2
87
20
56
82
44
56
27
0
84
86
73
97
S
R
R
R
R
a
b
Isolated yield. Determined by the specific rotation; Davis’ reagent ) (+)-[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine; TBHP ) tert-
butyl hydroperoxide; DET ) diethyl tartrate; CHP ) cumene hydroperoxide.
F igu r e 4. Time course of ee (%) of (R)-5.
F igu r e 5. Time course of yields of products in asymmetric
oxidation of 2.
pair rather than at the axial one, since the equatorially
oriented lone pair is relatively unhindered. Consequently,
stereochemical outcomes of bulky oxidants such as m-
CPBA, dimethyldioxirane, and HOSe(O)OH are con-
trolled by the reagent approach to give mainly the meso-
isomer.13 On the other hand, ozone is a small and highly
electrophilic oxidant and reacts more with a nucleophilic
lone pair rather than with a less hindered one.13 Since
the equatorial lone pair on the sulfide would be stabilized
by the anomeric effect resulting from an ns f σ*C-C(O)
interaction,16 the oxidation of the sulfide with ozone
proceeds at the reactive axial lone pair to give mainly
the desired trans-isomer.
Syn t h esis of Ch ir a l Au xilia r y via Asym m et r ic
Oxid a tion . We attempted to establish a more efficient
synthetic route to the mono-sulfoxide 5 via asymmetric
oxidation of 1,5-benzodithiepan-3-one (2). We examined
the representative methodologies developed by Davis,17
Kagan,18 and Modena.19 The results are summarized in
Table 1. Davis’ reagent and Kagan’s procedure were not
efficient for this substrate (entries 1 and 2), while
Modena’s procedure afforded better selectivities (entries
3 and 4). When 2 equiv of cumene hydroperoxide (CHP)
was used as an oxidant,20 the ee was increased up to 97%
(entry 6).
Sch em e 4
2 in 60% yield in one step. Since both enantiomers of
diethyl tartrate are available, this methodology can be
applied to the synthesis of (S)-5. In fact, (S)-5 was
synthesized in the same yield with high optical purity.
The enhancement of ee can be explained as follows
(Scheme 4). In this reaction, the rate of oxidation of the
main mono-sulfoxide (R)-5 is slower than that of bis-
sulfide 2. This indicates that the chiral oxidant and the
mono-sulfoxide (R)-5 are mismatched, while the matched
enantiomer (S)-5 would be promptly oxidized to bis-
sulfoxides (R,S)-1 (meso-form) rather than (S,S)-1. Thus,
the optical purity of the initially formed (R)-5 would be
enhanced by rapid consumption of the minor enantiomer
(S)-5.21 It is obvious that a kinetic resolution took place
in this reaction.
Ba se-P r om ot ed Dia st er eoselect ive Acet a l F is-
sion . With the chiral auxiliary in hand, we examined the
acetalization and asymmetric desymmetrization of meso-
1,2-diols (Scheme 5). We found that Terashima’s proce-
dure22 was suitable for acetalization of meso-diols using
the C2-symmetric bis-sulfoxide.23 Thus, the meso-1,2-diols
6a -e were acetalized with (R,R)- or (S,S)-bis-sulfoxide
1 in the presence of TMSOTf and 2,6-lutidine at 0 °C in
good yields to give the acetals 7a -e (Table 2). Only the
reaction of the nitrogen-containing meso-diol (the free
alcohol of 6f) was sluggish, resulting in a poor yield (4
°C, 82 h, 38%). This problem was overcome by employing
To determine the optimum conditions, we examined
the time course of the ee of (R)-5 and the product yields
(Figures 4 and 5). Although the ee of mono-sulfoxide (R)-5
was initially low (6 h, 40% ee), the ee increased and
reached a maximum value (36 h, >98% ee). During this
period, the yield of (R)-5 decreased. Alternatively, (R,S)-1
(meso) and (R,R)-1 (36 h, 70% ee) gradually increased.
Thus, optically pure (R)-5 was efficiently prepared from
(16) J uaristi, E.; Gonza´lez, E. A.; Pinto, B. M.; J ohnston, B. D.;
Nagelkerke, R. J . Am. Chem. Soc. 1989, 111, 6745-6749.
(17) Davis, F. A.; Reddy, R. T.; Weismiller, M. C. J . Am. Chem. Soc.
1989, 111, 5964-5965. Davis, F. A.; Reddy, R. T.; Han, W.; Carroll, P.
J . J . Am. Chem. Soc. 1992, 114, 1428-1437.
(21) A similar amplification of ee in the asymmetric oxidation of
sulfides has been reported previously, see: Komatsu, N.; Hashizume,
M.; Sugita, T.; Uemura, S. J . Org. Chem. 1993, 58, 4529-4533.
Aggarwal, V. K.; Esquivel-Zamora, B. N.; Evans, G. R.; J ones, E. J .
Org. Chem. 1998, 63, 7306-7310.
(22) Matsuda, F.; Terashima, S. Tetrahedron 1988, 44, 4721-4736.
(23) The reaction should be carried out below 5 °C to avoid partial
racemization of 1.
(18) Pitchen, P.; Dunach, E.; Deshmukh, N. N.; Kagan, H. B. J . Am.
Chem. Soc. 1984, 106, 8188-8193.
(19) Di Furia, F.; Modena, G.; Seraglia, R. Synthesis 1984, 325-
326.
(20) Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987, 43,
5135-5144. Kagan, H. B.; Rebiere, F. Synlett 1990, 643-650.

C2-Symmetric Bis-sulfoxide
Ta ble 2. Aceta liza tion of 6a -f
J . Org. Chem., Vol. 65, No. 11, 2000 3287
acetalization diol
X
acetal
yield (%)a
6a
6b
6c
6d
6e
6fc
(CH2)2
CH2
CHdCH
CH2CHdCHCH2
O
7a
86
83
89
90
80
89
7b
7cb
7d
7e
NCbz
7fb
a
b
c
Isolated yield. Acetalized with (S,S)-bis-sulfoxide. Mono-
TMS ether was employed.
Sch em e 5
F igu r e 6. Possible chelation intermediates of base-promoted
acetal fission.
Ta ble 3. Ba se-P r om oted Aceta l F ission of 7a
entry
conditions (equiv)a
yieldb (%)
dec (%)
1
2
3
4
5
6
LDA (3), 12-c-4 (3), THF
79
79
83
91
75
80
14
8
90
>96
>96
>96
LHMDS (3), 12-c-4 (3), THF
NaHMDS (3), 15-c-5 (3), THF
KHMDS (3), 18-c-6 (3), THF
KHMDS (3), 18-c-6 (3), DME
KHMDS (3), 18-c-6 (3), toluene
a
The reaction was carried out at -78 °C, and the resulting
b
alcohol was acetylated with acetic anhydride. Isolated yield after
acetylation. c Determined by 500 MHz 1H NMR spectroscopy.
matically increased in the order Li , Na < K (entries
1-4). The best results were obtained using 3 equiv of
KHMDS and 18-crown-6 in THF, which led to the
formation of acetate 8a -Ac in 91% chemical yield and
>96% ee (entry 4). No solvent effect on the selectivity
was observed (entries 4-6).
Taking account of the remarkable effect of the metal
cation on diastereoselectivity, we assumed a chelation-
controlled mechanism as shown in Figure 6. The potas-
sium cation would coordinate between polar sulfinyl
oxygen and the axially oriented acetal oxygen to form the
six-membered ring chelation intermediates. Since the
intermediates B and C giving minor products have
congested structures, the reaction would proceed via
intermediate A which has the least steric demand. Thus,
the major products would be formed via stereoelectroni-
cally favorable anti-elimination through path a or b. This
speculation regarding the favorable conformation was
supported by the X-ray structure of racemic acetal (()-7c
(Figure 7), which was almost consistent with that of
chelation intermediate A. The coordination of the sodium
or potassium cation would stabilize the preferred con-
formation, thereby giving high diastereoselectivity. On
the other hand, the lower selectivity observed in LHMDS
could be attributed to the short atomic radius of the
lithium cation, which could not stabilize the preferred
conformation by the chelation.
Various meso-diols were desymmetrized with very high
and predictable diastereoselectivities via base-promoted
acetal fission of 7a -f to give 8a -f, respectively, after
trapping the resulting alkoxides as the acetates or benzyl
ethers (Table 4). When (R,R)-1 is used as a chiral
auxiliary, the stereochemistry of the resulting alkoxides
have an S-configuration.26 On the other hand, acetaliza-
tion of the acyclic meso-1,2-diols, meso-erythrytol 1,4-
dibenzyl ether, was sluggish and caused decomposition
of the bis-sulfoxide, although the diastereoselectivity of
acetal fission was very high (>96% de).
mono-TMS ether 6f in the presence of TMSOTf in CHCl3
to give a good yield of 7f (4 °C, 6 h, 89%).
Base-promoted acetal fission of 7a with LDA or LH-
MDS and 12-crown-424 followed by acetylation of the
resulting alkoxide to prevent recyclization afforded 8a -
Ac in good yield, but with poor diastereoselectivity (Table
3, entries 1 and 2).25 Interestingly, the countercation in
the base had a remarkable effect. Selectivity was dra-
(24) In the absence of crown ether, the acetate 8a -Ac was formed
in a poor yield (56%) and a considerable amount of acetal 7a was
recovered (28%).
(25) After the addition of the base, the reaction was quenched
with acetic anhydride at -78 °C, and the mixture was transferred
into a saturated NH4Cl aqueous solution. This workup was essential
to prevent undesirable recyclization of the product. The partially
acetylated product was filtrated through a short pad of silica gel and
then completely acetylated with acetic anhydride and DMAP.

3288 J . Org. Chem., Vol. 65, No. 11, 2000
Maezaki et al.
commercially available 1,2-benzenedithiol in three steps
via asymmetric oxidation. Because of its C2 symmetry,
the formation of diastereomeric isomers at the acetal-
ization step can be avoided. In addition, its ability to
differentiate was high enough to be used as a complement
to the enzymatic method. Our method affords a powerful
tool for the synthesis of natural products.
Exp er im en ta l Section
All melting points are uncorrected. NMR spectra were
recorded in a CDCl3 solution at 500 MHz (1H) and 75 MHz
(13C). IR absorption spectra (FT: diffuse reflectance spectros-
copy) were recorded with KBr powder, and only noteworthy
absorptions (cm-1) are listed. Column chromatography was
carried out using Merck silica gel 60 (70-230 mesh). All air-
or moisture-sensitive reactions were carried out in flame-dried
glassware under an atmosphere of Ar or N2. All solvents were
dried and distilled according to standard procedures. All
organic extracts were dried over anhydrous MgSO4, filtered,
and concentrated with a rotary evaporator under reduced
pressure.
1,5-Ben zod ith iep a n -3-on e (2). A solution of 1,3-dichloro-
acetone (10.3 g, 81.4 mmol) in CH2Cl2 (100 mL) was added to
a solution of 1,2-benzenedithiol (10.5 g, 74.0 mmol) and DMAP
(19.9 g, 162 mmol) in CH2Cl2 (750 mL) with stirring at -30
°C under N2. After 5 min at -30 °C, the reaction was quenched
with 1 N HCl and the organic layer was washed with water
and brine prior to drying and solvent evaporation. The residue
was chromatographed on silica gel with hexane-AcOEt (1:1)
to give 2 (11.1 g, 76%) as a colorless powder. Mp: 76.0-77.0
°C (hexane-AcOEt). 1H NMR δ: 3.60 (s, 4H), 7.28 (dd, 2H,
J ) 6.0, 3.4 Hz), 7.68 (dd, 2H, J ) 6.0, 3.4 Hz). 13C NMR δ:
41.9 (2C), 128.7 (2C), 133.5 (2C), 138.6 (2C), 202.9. IR 1713,
1680. MS m/z (%): 196 (M+, 65.7), 153 (100). Anal. Calcd for
C9H8OS2: C, 55.07; H, 4.11; S, 32.67. Found: C, 55.05; H, 4.11;
S, 32.62.
F igu r e 7. ORTEP drawing of ent-7c. (a) Top view. (b) Side
view.
Ta ble 4. Dia ster eoselective Aceta l F ission of Aceta ls
7a -f
yield de
(%)b (%)c confignd
acetal
X
methoda product
R
7a
(CH2)2
CH2
CHdCH
CH2CHdCHCH2
A
B
A
B
A
B
B
8a -Ac Ac 91 >96 (1R,2S)
8a -Bn Bn 92 >96 (1R,2S)
7b
7c
7d
7e
7f
8b
8c
8d
8e
8f
Ac 78 >96 (1R,2S)
Bn 85 >96 (1S,2R)e
Ac 89
91 (1R,2S)
O
NCbz
Bn 71 >96 (1R,2S)
Bn 84 >96 (1S,2R)e
a
(4′R,5′R)-Sp ir o[1,5-ben zod ith iep a n e-3,2′-[4,5]d ieth oxy-
car bon yl[1,3]dioxolan e] (3). Trimethylsilyl trifluoromethane-
sulfonate (4.92 mL, 25.5 mmol) was added slowly to a solution
of 2 (10.0 g, 50.9 mmol) and (+)-diethyl tartrate bis-trimethyl-
silyl ether (18.8 g, 53.5 mmol) in CH2Cl2 (500 mL) with stirring
at rt under N2. The whole was refluxed for 1 h. After cooling,
the mixture was partitioned between CH2Cl2 and saturated
NaHCO3. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers
were washed with water and brine prior to drying and solvent
evaporation. The crude was chromatographed on silica gel with
hexane-AcOEt (5:1) to give 3 (19.0 g, 97%) as a colorless
Method A, (i) KHMDS (3), 18-c-6 (3), THF, -78 °C, then Ac2O;
(ii) DMAP, Ac2O, CH2Cl2, 0 °C f rt; Method B, KHMDS (3),
b
18-c-6 (3), THF, -78 °C, then BnBr. Isolated yield. c Determined
d
by 500 MHz 1H NMR spectroscopy. See ref 26. e (S,S)-1 was used
as a chiral auxiliary.
Sch em e 6
powder. Mp: 74.5-75.0 °C (hexane-AcOEt). [R]25 -21.6 (c
D
1
1.01, CHCl3). H NMR δ: 1.34 (t, 6H, J ) 7.3 Hz), 3.15 (br s,
The chiral auxiliary could be removed by acid hydroly-
sis with 10% HCl in acetone in good yield, as shown in
Scheme 6. The chiral auxiliary (S,S)-1 was recovered in
81% chemical yield without decreasing the enantiomeric
excess (>98% ee) and was reusable.
4H), 4.27-4.33 (m, 4H), 4.91 (s, 2H), 7.18-7.20 (m, 2H), 7.59
(br s, 2H). 13C NMR δ: 14.0 (2C), 40.5 (2C), 62.1 (2C), 78.0
(2C), 114.1, 128.0 (2C), 133.3 (2C), 139.7 (2C), 169.3 (2C). IR
1755, 1739. MS m/z (%): 384 (M+, 8.7), 154 (100). Anal. Calcd
for C17H20O6S2: C, 53.11; H, 5.24; S, 16.68. Found: C, 52.88;
H, 5.17; S, 16.61.
(1R,4′R,5′R)- a n d (1S,4′R,5′R)-Sp ir o[1,5-b en zod it h ie-
p a n e-3,2′-[4,5]d ieth oxyca r bon yl-[1,3]d ioxola n e] 1-Oxid e
(4a a n d 4b). m-CPBA (8.11 g, 37.6 mmol) was added to a
solution of 3 (14.5 g, 37.6 mmol) in CH2Cl2 (350 mL) with
stirring at rt, and the whole was stirred at rt for 2 h. The
mixture was washed with saturated NaHCO3, water, and brine
prior to drying and solvent evaporation. The residue was
chromatographed on silica gel with hexane-AcOEt (1:1) to give
4a (6.76 g, 45%) and 4b (7.79 g, 52%) each as a colorless
Con clu sion
We developed a novel C2-symmetric bis-sulfoxide, 1,
which was found to be an efficient chiral auxiliary for
the asymmetric desymmetrization of cyclic meso-1,2-diols
via acetalization followed by highly diastereoselective
acetal fission. This unique heterocyclic compound 1 can
be readily synthesized with high optical purity from
powder. 4a (less polar): mp 113.5-114.0 °C (hexane-AcOEt).
1
[R]28 +82.6 (c 1.11, CHCl3). H NMR δ: 1.34 (t, 3H, J ) 7.3
(26) The absolute configurations of the benzyl ethers 8a -Bn , 8c, and
8e-f were established by Mosher’s method after removal of the chiral
auxiliary with 10% HCl followed by conversion into the MTPA esters.
Those of the acetates 8a -Ac and 8b were determined by Mosher’s
method after converting the alkoxides from 7a and 7b into the
corresponding MTPA esters. The stereochemistry of 8d was assumed
by analogy with others: Dale, J . A.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543-2549; J . Am. Chem. Soc. 1973, 95, 512-519.
D
Hz), 1.36 (t, 3H, J ) 7.3 Hz), 2.58 (d, 1H, J ) 15.4 Hz), 3.16
(dd, 1H, J ) 15.4, 2.6 Hz), 3.33 (d, 1H, J ) 12.8 Hz), 3.56 (dd,
1H, J ) 12.8, 2.6 Hz), 4.27-4.35 (m, 4H), 4.90 (d, 1H, J ) 3.4
Hz), 5.08 (d, 1H, J ) 3.4 Hz), 7.44-7.47 (m, 1H), 7.63-7.66
(m, 2H), 7.90 (d, 1H, J ) 7.7 Hz). 13C NMR δ: 14.1 (2C), 42.3,
62.4 (2C), 64.8, 78.2, 78.5, 111.8, 124.8, 130.2, 130.3, 130.6,

C2-Symmetric Bis-sulfoxide
J . Org. Chem., Vol. 65, No. 11, 2000 3289
134.9, 151.4, 168.7, 169.2. IR 1757, 1740, 1059. MS m/z (%):
400 (M+, 3.9), 243 (100). Anal. Calcd for C17H20O7S2: C, 50.99;
H, 5.03; S, 16.01. Found: C, 50.98; H, 4.96; S, 15.85. 4b (more
X-ray crystallographic analysis, and their dimensions were 0.5
× 0.5 × 1.0 mm3. Crystallographic data of (R,R)-1 are as
follows: C9H8O3S2, MW ) 228.28, orthorhombic, space group
P212121 with the cell dimensions a ) 8.16(1) Å, b ) 16.448(6)
Å, c ) 7.130(5) Å, V ) 957(1) A3, Z ) 4, density(calcd) ) 1.58
g cm-3, F(000) ) 472, λ ) 1.5418 Å, T ) 293 K, µ(Cu KR) )
4.804 cm-1. Intensity data were collected on a Rigaku AFC7R
diffractometer using monochromated Cu KR radiation. The
data were obtained up to 0.86 Å resolution. The 2θ value was
125°; 976 unique reflections were observed. The 960 reflections
with I > 3.00σ(I) were used in refinement: the final R value
was 8.32%.
polar): mp 106.0-107.0 °C (hexane-AcOEt). [R]27 -161.3 (c
D
1
1.01, CHCl3). H NMR δ 1.33 (t, 3H, J ) 7.1 Hz), 1.44 (t, 3H,
J ) 7.1 Hz), 2.67 (d, 1H, J ) 15.0 Hz), 3.22 (dd, 1H, J ) 15.0,
2.6 Hz), 3.27 (d, 1H, J ) 12.8 Hz), 3.48 (dd, 1H, J ) 12.8, 2.6
Hz), 4.29 (q, 2H, J ) 7.1 Hz), 4.39-4.43 (m, 2H), 4.97 (d, 1H,
J ) 4.3 Hz), 4.99 (d, 1H, J ) 4.3 Hz), 7.44-7.48 (m, 1H), 7.64-
7.67 (m, 2H), 7.90 (d, 1H, J ) 6.9 Hz). 13C NMR δ: 14.1 (2C),
42.5, 62.4, 62.9, 64.4, 78.0, 78.7, 111.6, 124.7, 130.0, 130.3,
130.7, 135.1, 151.7, 168.9, 169.2. IR 1753, 1736, 1061. MS m/z
(%): 400 (M+, 4.7), 243 (100). Anal. Calcd for C17H20O7S2: C,
50.99; H, 5.03; S, 16.01. Found: C, 50.96; H, 4.97; S, 15.96.
The colorless needle crystals of racemic 4a were grown from
a hexane-AcOEt solution. The crystals were suitable for X-ray
crystallographic analysis, and their dimensions were 0.2 × 0.2
× 0.3 mm3. Crystallographic data of 4a are as follows:
C17H20O7S2, MW ) 400.46, monoclinic, space group P21
with the cell dimensions a ) 5.427(2) Å, b ) 15.858(1) Å, c )
11.021(1) Å, â ) 95.82°(2), V ) 944(1) A3, Z ) 2, density(calcd)
) 1.41 g cm-3, F(000) ) 420, λ ) 1.5418 Å, T ) 293 K, µ(Cu
KR) ) 2.829 cm-1. Intensity data were collected on a Rigaku
AFC5R diffractometer using monochromated Cu KR radiation.
The data were obtained up to 0.89 Å resolution. The 2θ value
was 120°; 1643 unique reflections were observed. The 1507
reflections with I > 3.00σ(I) were used in refinement: the final
R value was 7.06%.
(1S,5S)-1,5-Ben zod ith iep a n e-3-on e 1,5-Dioxid e [(S,S)-
1]. Using the procedure for (R,R)-1 from (R)-5, (S)-5 (1.31 g,
6.18 mmol) was converted into (S,S)-1 (641 mg, 46%) as a
colorless powder along with (R,S)-1 (meso) (263 mg, 19%) and
(S)-5 (86 mg, 7%). Mp: 194.0-195.0 °C (dec) (hexane-AcOEt).
[R]30 +98.5 (c 0.34, CHCl3). Anal. Calcd for C9H8O3S2: C,
D
47.35; H, 3.53; S, 28.09. Found: C, 47.23; H, 3.53; S, 27.89.
Asym m etr ic Oxid a tion of 1,2-Ben zod ith iep a n -3-on e (2)
(Ta ble 1). Usin g Da vis’ Rea gen t (En tr y 1). A solution of
[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine (77.9 mg, 0.261
mmol) in CH2Cl2 (3.0 mL) was added to a solution of 3 (51.3
mg, 0.261 mmol) in CH2Cl2 (5.0 mL) with stirring at -20 °C
under N2. The stirring was continued at rt for 3 d. Saturated
NaHCO3 was added to the mixture. After 1 h, the mixture was
extracted with CHCl3 and the extract was washed with brine
prior to drying and solvent evaporation. The crude was
chromatographed on silica gel with hexane-AcOEt (1:1) to give
(R)-1,5-Ben zod ith iep a n -3-on e 1-Oxid e [(R)-5]. KHMDS
(0.5 M toluene solution, 0.310 mL, 0.155 mmol) was added
dropwise to a solution of 4a (41.4 mg, 0.103 mmol) in THF
(4.0 mL) with stirring at -78 °C under N2. After 15 min, the
reaction was quenched with saturated NH4Cl and the resulting
mixture was extracted with AcOEt. The extracts were washed
with water and brine prior to drying and solvent evaporation.
The residue was chromatographed on silica gel with hexane-
AcOEt (3:2) to give (R)-5 (18.3 mg, 83%) as a colorless powder.
(S)-5 [48 mg, 87%, [R]25 -6.7 (c 0.93, CHCl3), 27% ee] as a
D
colorless powder.
Usin g a Mod ified Sh a r p less Ep oxid a tion Rea gen t
(Gen er a l P r oced u r e) (En tr y 6). A solution of 2 (101.2 mg,
0.516 mmol) in CH2Cl2 (2.0 mL) was added to a mixture of
Ti(O-i-Pr)4 (1 M in CH2Cl2) (0.516 mL, 0.516 mmol) and (+)-
diethyl tartrate (0.353 mL, 2.06 mmol) in CH2Cl2 (5.0 mL) with
stirring at rt. Cumene hydroperoxide (0.190 mL, 1.03 mmol)
was slowly added to the mixture, and stirring was continued
at -20 °C for 2 d. The reaction was quenched with a 5%
aqueous Na2SO3 solution, and the whole was stirred for 30
min at rt. The mixture was extracted with CHCl3. After the
addition of 10% hydrochloric acid, the mixture was washed
with 5% Na2SO3 and saturated NaHCO3 prior to drying and
solvent evaporation. The crude was chromatographed on silica
gel using hexane-AcOEt (1:1) to give (R)-5 [61.4 mg, 56%,
Mp: 135.0-136.0 °C (hexane-AcOEt). [R]27 +24.1 (c 0.94,
D
1
CHCl3). H NMR δ: 3.29 (d, 1H, J ) 13.7 H), 3.45 (dd, 1H, J
) 13.7, 1.7 Hz), 3.76 (d, 1H, J ) 11.1 Hz), 4.38 (dd, 1H, J )
11.1, 1.7 Hz), 7.54 (dt, 1H, J ) 7.7, 1.7 Hz), 7.67 (d, 1H, J )
7.7 Hz), 7.72 (dt, 1H, J ) 7.7, 1.7 Hz), 7.96 (dd, 1H, J ) 7.7,
1.7 Hz). 13C NMR δ: 45.7, 68.3, 126.3, 129.3, 131.2, 131.6,
135.5, 150.3, 191.3. IR 1701, 1605. MS m/z (%): 212 (M+, 14.3),
153 (36.9), 140 (100). HRMS calcd for C9H8O2S2: 211.9966.
Found: 211.9974.
[R]28 +23.4 (c 1.04, CHCl3), 97% ee] as a colorless powder.
D
(S)-1,5-Ben zod ith iep a n -3-on e 1-Oxid e [(S)-5]. Using the
procedure for (R)-5 from 4a , 4b (5.86 g, 14.6 mmol) was
converted into (S)-5 (2.76 g, 89%). Mp: 138.5-139.0 °C
(hexane-AcOEt). [R]30D -24.6 (c 1.00, CHCl3). Anal. Calcd for
C9H8O2S2: C, 50.92; H, 3.80; S, 30.21. Found: C, 50.82; H,
3.73; S, 30.06.
Gen er a l P r oced u r e for Aceta liza tion . 2,6-Lutidine (32
µL, 0.27 mmol) was added to a solution of (1R,5R)-1 (20.7 mg,
0.0907 mmol) and cis-cyclohexane-1,2-diol (31.6 mg, 0.272
mmol) in CH2Cl2 (3.5 mL) with stirring at 0 °C under N2. After
5 min, trimethylsilyl trifluoromethanesulfonate (70 µL, 0.36
mmol) was added dropwise. Stirring was continued at 0 °C
for 4 h. The reaction was quenched with saturated NaHCO3,
and the mixture was extracted with CH2Cl2. The extracts were
washed with brine prior to drying and solvent evaporation.
The crude was chromatographed on silica gel with AcOEt to
give 8a (25.4 mg, 86%) as a colorless powder.
(1R,5R)-Sp ir o[1,5-b en zod it h iep a n e-3,8′-[7,9]d ioxa b i-
cyclo[4.3.0]n on a n e] 1,5-Dioxid e (7a ). Yield: 86% (colorless
powder). Mp: 196.0-198.0 °C (acetone). [R]20D +164.7 (c 0.45,
MeOH). 1H NMR δ: 1.25-1.30 (m, 2H), 1.45-1.54 (m, 2H),
1.66-1.78 (m, 4H), 3.88 (d, 1H, J ) 2.6 Hz), 3.40 (d, 1H, J )
2.6 Hz), 3.55 (d, 1H, J ) 13.7 Hz), 3.61 (d, 1H, J ) 13.7 Hz),
4.19-4.20 (m, 2H), 7.64 (dt, 1H, J ) 7.7, 1.7 Hz), 7.68 (dt, 1H,
J ) 7.7, 1.7 Hz), 7.87 (dd, 1H, J ) 7.7, 1.7 Hz), 7.96 (d, 1H, J
) 7.7 Hz). 13C NMR δ: 20.5, 20.5, 27.9, 28.2, 61.2, 63.1, 74.5,
74.6, 104.4, 126.2, 126.5, 131.2, 131.8, 142.2, 143.9. IR 1059.
MS m/z (%): 326 (M+, 2.0), 180 (27.6), 153 (28.6), 140 (49.6),
81 (100). Anal. Calcd for C15H18O4S2: C, 55.19; H, 5.56; S,
19.65. Found: C, 54.89; H, 5.45; S, 19.34.
(1R,5R)-1,5-Ben zod ith iep a n e-3-on e 1,5-Dioxid e [(R,R)-
1]. Ozone was passed through (R)-5 (950 mg, 4.16 mmol)
absorbed on silica gel (20 g) at -78 °C for 15 min. Then, the
whole was allowed to stand at -20 °C for 45 min. After the
protocol was repeated five times, the excess ozone was removed
by blowing an N2 stream through the solution. The mixture
was packed on a chromatography column and eluted with
hexane-AcOEt (2:1) to give (R,R)-1 (475 mg, 47%) and (R,S)-1
(154 mg, 15%), each as a colorless powder. (R,R)-1: mp 195.0-
196.0 °C (dec) (hexane-AcOEt). [R]25D -100.3 (c 0.29, CHCl3).
1H NMR δ: 4.03 (d, 2H, J ) 12.0 Hz), 4.31 (d, 2H, J ) 12.0
Hz), 7.74-7.78 (m, 2H), 7.98-8.02 (m, 2H). 13C NMR δ: 68.2
(2C), 126.7 (2C), 132.4 (2C), 143.2 (2C), 189.3. IR 1697, 1064.
MS m/z (%): 228 (M+, 12.1), 121 (100). Anal. Calcd for
C9H8O3S2: C, 47.35; H, 3.53; S, 28.09. Found: C, 47.06; H,
3.56; S, 27.87. (R,S)-1: colorless powder; mp 221.5-222.5 °C
1
(AcOEt-MeOH). H NMR δ: 3.76 (d, 2H, J ) 11.5 Hz), 4.48
(d, 2H, J ) 11.5 Hz), 7.84-7.86 (m, 2H), 8.12-8.14 (m, 2H).
13C NMR δ: 69.6 (2C), 123.6 (2C), 132.5 (2C), 139.7 (2C), 187.0.
IR 1701, 1076. MS m/z (%): 228 (M+, 28.4), 108 (100). HRMS
calcd for C9H8O3S2: 227.9915. Found: 227.9915.
(1R,5R)-Sp ir o[1,5-b en zod it h iep a n e-3,3′-[2,4]d ioxa b i-
cyclo[3.3.0]octa n e] 1,5-Dioxid e (7b). Yield: 83% (colorless
powder). Mp: 207.0-208.5 °C (acetone-MeOH). [R]25D +198.9
(c 0.38, MeOH). 1H NMR δ: 1.39-1.49 (m, 2H), 1.57-1.64 (m,
2H), 1.77-1.81 (m, 1H), 1.92-1.96 (m, 1H), 3.16 (d, 1H, J )
The colorless prism crystals of racemic (R,R)-1 were grown
from a hexane-AcOEt solution. The crystals were suitable for

3290 J . Org. Chem., Vol. 65, No. 11, 2000
Maezaki et al.
15.0 Hz), 3.29 (d, 1H, J ) 13.7 Hz), 3.56 (d, 1H, J ) 15.0 Hz),
3.64 (d, 1H, J ) 13.7 Hz), 4.69 (t, 1H, J ) 5.6 Hz), 4.77 (t, 1H,
J ) 5.6 Hz), 7.62 (t, 1H, J ) 7.7 Hz), 7.71 (dt, 1H, J ) 7.7, 1.7
Hz), 7.80 (d, 1H, J ) 7.7 Hz), 8.03 (d, 1H, J ) 7.7 Hz). 13C
NMR δ: 22.2, 33.0, 33.1, 59.9, 60.3, 81.7, 82.0, 105.6, 126.3,
126.4, 130.9, 132.2, 140.9, 144.9. IR 1067. MS m/z (%): 312
(M+, 2.0), 126 (60), 67 (100). Anal. Calcd for C14H16O4S2: C,
53.83; H, 5.16; S, 20.53. Found: C, 53.66; H, 5.09; S, 20.45.
(1S,5S)-Sp ir o[1,5-b en zod it h iep a n e-3,8′-[7,9]d ioxa b i-
cyclo[4.3.0]n on -3-en e] 1,5-Dioxid e (7c). Yield: 89% (color-
12.8, 4.3 Hz), 3.51-3.53 (m, 1H), 3.73 (d, 1H, J ) 12.2 Hz),
3.83 (br s, 1H), 3.91 (d, 1H, J ) 13.4 Hz), 4.78 (br s, 1H), 4.86
(t, 1H, J ) 5.2 Hz), 5.13 (s, 2H), 7.32-7.39 (m, 5H), 7.60 (t,
1H, J ) 7.6 Hz), 7.71-7.74 (m, 2H), 8.06 (br s, 1H). 13C NMR
δ: 51.6, 51.9, 59.4 (1/2C), 60.4 (1/2C), 61.0 (1/2C), 62.2 (1/2C),
67.3, 79.6, 80.2, 107.9, 126.3 (2C), 128.1 (2C), 128.2, 128.5 (2C),
130.9, 132.4, 136.3, 139.6 (1/2C), 140.8 (1/2C), 144.6 (1/2C),
145.5 (1/2C), 155.0. IR 1703, 1063. MS m/z (%): 447 (M+, 0.9),
149 (100). HRMS calcd for C21H21NO6S2: 447.0810. Found:
447.0816.
less powder). Mp: 210.5-212.0 °C (hexane-AcOEt). [R]26
Gen er a l P r oced u r e of Acet a l F ission . Met h od A:
(1R,5R)-3-[[(1R,2S)-2-(Acet oxy)cycloh exyl]oxy]-4H -1,5-
ben zod ith iep in e 1,5-Dioxid e (8a -Ac). KHMDS (0.5 M tolu-
ene solution) (0.24 mL, 0.119 mmol) was added to a solution
of acetal 7a (13.0 mg, 0.039 mmol) and 18-crown-6 (31.6 mg,
0.119 mmol) in THF (4 mL) with stirring at -78 °C under N2.
After 15 min, acetic anhydride (23.0 µL, 0.120 mmol) was
added and the mixture was poured onto saturated NH4Cl. The
aqueous layer was extracted with AcOEt, and the extracts
were washed with saturated NaHCO3, water, and brine prior
to drying and solvent evaporation. Acetic anhydride (11 µL,
0.12 mmol) was added dropwise to the mixture of the crude
and DMAP (13.5 mg, 0.119 mmol) in CH2Cl2 (1 mL) with
stirring at rt, and the whole was stirred at rt for 10 min. After
the addition of water, the mixture was extracted with CH2-
Cl2. The extracts were washed with brine prior to drying and
solvent evaporation. The crude was chromatographed on silica
gel with AcOEt to give 8a -Ac (13.4 mg, 91%) as a colorless
D
-226.5 (c 0.50, CHCl3). 1H NMR δ: 2.12-2.22 (m, 3H), 2.30-
2.35 (m, 1H), 3.19 (d, 1H, J ) 14.0 Hz), 3.33 (d, 1H, J ) 13.4
Hz), 3.54 (d, 1H, J ) 14.0 Hz), 3.61 (d, 1H, J ) 13.4 Hz), 4.48-
4.57 (m, 2H), 5.74-5.79 (m, 2H), 7.62 (t, 1H, J ) 7.3 Hz),
7.70 (t, 1H, J ) 7.3 Hz), 7.81 (d, 1H, J ) 7.9 Hz), 8.01 (d,
1H, J ) 7.3 Hz). 13C NMR δ: 27.6, 27.8, 60.9, 61.2, 74.2, 74.3,
104.5, 125.4, 125.5, 126.3, 126.3, 131.0, 131.9, 141.5, 144.5.
IR 1059. MS m/z (%): 324 (M+, 87), 79 (100). Anal. Calcd for
C
15H16O4S2: C, 55.53; H, 4.97; S, 19.77. Found: C, 55.34; H,
4.97; S, 19.49.
The colorless needle crystals of racemic 7c were grown from
a hexane-AcOEt solution. The crystals were suitable for X-ray
crystallographic analysis, and their dimensions were 0.6 × 0.4
× 0.3 mm3. Crystallographic data of 7c are as follows:
C
15H16O4S2, MW ) 324.40, triclinic, space group P-1 with cell
dimensions a ) 11.979(2) Å, b ) 12.001(1) Å, c ) 5.250(4) Å,
R ) 99.45°(2), â ) 94.78°(1), γ ) 102.60(1), V ) 720.9(5) A3,
Z ) 2, density(calcd) ) 1.49 g cm-3, F(000) ) 340, λ ) 1.5418
Å, T ) 293 K, µ(Cu KR) ) 4.804 cm-1. Intensity data were
collected on a Rigaku AFC5R diffractometer using monochro-
mated Cu KR radiation. The data were obtained up to 0.86 Å
resolution. The 2θ value was 125°; 2312 unique reflections
were observed. The 2035 reflections with I > 2.00σ(I) were
used in refinement: the final R value was 10.57%.
oil. [R]27 -94.1 (c 0.75, CHCl3). 1H NMR δ: 1.37-1.43 (m,
D
2H), 1.53-1.68 (m, 4H), 1.82-1.85 (m, 1H), 1.90-1.92 (m, 1H),
1.95 (s, 3H), 4.09 (d, 1H, J ) 15.8 Hz), 4.29-4.31 (m, 1H),
4.36 (d, 1H, J ) 15.8 Hz), 4.91-4.94 (m, 1H), 5.87 (s, 1H),
7.63 (t, 1H, J ) 7.7 Hz), 7.69 (t, 1H, J ) 7.7 Hz), 7.86 (d, 1H,
J ) 7.7 Hz), 8.00 (dd, 1H, J ) 7.7, 1.7 Hz). 13C NMR δ: 20.9,
21.0, 21.8, 26.7, 27.1, 56.5, 70.8, 75.9, 109.6, 125.2, 129.1, 131.5,
131.9, 141.7, 144.7, 152.7, 170.3. IR 1736, 1059. MS m/z (%):
368 (M+, 1.5), 99 (100), 81 (82). HRMS calcd for C17H20O5S2:
368.0750. Found: 368.0739.
(1R,5R)-Sp ir o[1,5-b en zod it h iep a n e-3,10′-[9,11]d ioxa -
bicyclo[6.3.0]u n d eca -4-en e] 1,5-Dioxid e (7d ). Yield: 90%
(colorless powder). Mp: 280.5-282.0 °C (MeOH). [R]26D +205.4
(c 0.52, CHCl3). 1H NMR δ: 1.79-1.85 (m, 1H), 1.89-1.94 (m,
1H), 1.98-2.06 (m, 4H), 2.43-2.48 (m, 2H), 3.31 (d, 1H, J )
13.9 Hz), 3.32 (d, 1H, J ) 13.9 Hz), 3.52 (d, 1H, J ) 13.9 Hz),
3.60 (d, 1H, J ) 13.9 Hz), 4.29-4.32 (m, 2H), 5.56 (s, 2H),
7.62 (t, 1H, J ) 6.8 Hz), 7.68 (d, 1H, J ) 7.7 Hz), 7.83 (d, 1H,
J ) 6.8 Hz), 7.97 (d, 1H, J ) 7.7 Hz). 13C NMR δ: 23.3 (2C),
28.0, 28.1, 61.2, 62.8, 79.2 (2C), 102.9, 126.2, 126.4, 128.9 (2C),
131.0, 131.8, 141.8, 144.0. IR 1063. MS m/z (%): 352 (M+, 28),
107 (82), 79 (100). HRMS calcd for C17H20O4S2: 352.0803.
Found: 352.0791.
Meth od B: (1R,5R)-3-[[(1R,2S)-2-(Ben zyloxy)cycloh exyl]-
oxy]-4H-1,5-ben zod ith iep in e 1,5-Dioxid e (8a -Bn ). KH-
MDS (0.5 M toluene solution) (0.206 mL, 0.103 mmol) was
added to a solution of acetal 7a (11.2 mg, 0.0343 mmol) and
18-crown-6 (27.2 mg, 0.103 mmol) in THF (3.5 mL) with
stirring at -78 °C under N2. After 5 min, benzyl bromide (4.1
µL, 0.034 mmol) was added to the mixture, and the whole was
stirred for 15 min at -78 °C. The reaction was quenched with
saturated NH4Cl, and the mixture was extracted with AcOEt.
The extracts were washed with water and brine prior to drying
and solvent evaporation. The crude was chromatographed on
silica gel with AcOEt to give 8a -Bn (13.2 mg, 92%) as a
(1R,5R)-Sp ir o[1,5-b en zod it h iep a n e-3,3′-[2,4,8]t r ioxa -
bicyclo[3.3.0]octa n e] 1,5-Dioxid e (7e). CHCl3 was used was
a solvent. Yield: 80% (colorless powder). Mp: 233.0-233.5 °C
colorless oil. [R]29 -44.0 (c 1.11, CHCl3). 1H NMR δ: 1.23-
D
(hexane-AcOEt). [R]26 +159.7 (c 0.28, CHCl3).1H NMR δ:
1.34 (m, 2H), 1.45-1.56 (m, 3H), 1.65-1.71 (m, 1H), 1.82-
1.89 (m, 1H), 1.90-1.96 (m, 1H), 3.60 (dt, 1H, J ) 7.9, 3.1
Hz), 4.12 (d, 1H, J ) 15.6 Hz), 4.18-4.20 (m, 1H), 4.25 (d, 1H,
J ) 15.6 Hz), 4.45 (d, 1H, J ) 12.5 Hz), 4.56 (d, 1H, J ) 12.5
Hz), 5.81 (s, 1H), 7.24-7.32 (m, 5H), 7.63 (dt, 1H, J ) 7.6, 1.2
Hz), 7.68 (dt, 1H, J ) 7.6, 1.2 Hz), 7.87 (dd, 1H, J ) 7.3, 1.2
Hz), 7.97 (dd, 1H, J ) 7.3, 1.2 Hz). 13C NMR δ: 21.4, 21.8,
26.4, 27.5, 56.6, 70.9, 75.2, 77.7, 110.1, 125.1, 127.5 (2C), 127.6,
128.4 (2C), 129.3, 131.5, 131.7, 138.4, 141.7, 145.0, 152.5. IR
1606, 1059. MS (FAB) m/z: 417 (M + H)+. HRMS (FAB) calcd
for C22H24O4S2 + H+: 417.1195. Found: 417.1197.
D
3.31 (d, 1H, J ) 13.4 Hz), 3.35-3.38 (m, 2H), 3.41 (dd, 1H, J
) 11.0, 3.7 Hz), 3.64 (d, 1H, J ) 13.4 Hz), 3.70 (d, 1H, J )
14.0 Hz), 3.94 (d, 1H, J ) 11.0 Hz), 4.10 (d, 1H, J ) 11.0 Hz),
4.86 (dd, 1H, J ) 6.1, 3.7 Hz), 4.93 (dd, 1H, J ) 5.5, 4.0 Hz),
7.63 (t, 1H, J ) 7.6 Hz), 7.71 (t, 1H, J ) 7.6 Hz), 7.81 (d, 1H,
J ) 7.3 Hz), 8.03 (d, 1H, J ) 7.3 Hz). 13C NMR δ: 59.9, 61.9,
73.4, 73.6, 81.7, 81.8, 108.2, 126.2, 126.3, 131.1, 132.0, 141.4,
144.2. IR 1643, 1063. MS (FAB) m/z: 315 (M+H)+. HRMS
(FAB) calcd for C13H14O5S2 + H+: 315.0361. Found: 315.0368.
(1S,5S)-Sp ir o[1,5-ben zod ith iep a n e-3,7′-[3′-(ben zyloxy-
ca r bon yl)-[3]a za -[6,8]d ioxa bicyclo[3.3.0]octa n e]] 1,5-Di-
oxid e (7f). Trimethylsilyl trifluoromethanesulfonate (74 µL,
0.38 mmol) was added to a solution of (1S,5S)-1 (87.0 mg, 0.38
mmol) and cis-1-(benzyloxycarbonyl)pyrrolidine-3,4-diol mono-
trimethylsilyl ether (300 mg, 1.15 mmol) in CHCl3 (1.74 mL)
with stirring at 0 °C under N2. Stirring was continued at 4 °C
for 6 h. The reaction was quenched with saturated NaHCO3,
and the mixture was extracted with CHCl3. The extracts were
washed with brine prior to drying and solvent evaporation.
The crude was chromatographed on silica gel with AcOEt to
(1R,5R)-3-[[(1R,2S)-2-(Acet oxy)cyclop en t yl]oxy]-4H -
1,5-ben zod ith iep in e 1,5-Dioxid e (8b). Yield: 78% (colorlss
1
oil). [R]30 -104.6 (c 0.50, CHCl3). H NMR δ: 1.56-1.61 (m,
D
1H), 1.78-1.88 (m, 3H), 1.91 (s, 3H), 1.94-2.00 (m, 2H), 3.94
(d, 1H, J ) 15.9 Hz), 4.41 (d, 1H, J ) 15.9 Hz), 4.48-4.50 (m,
1H), 5.00-5.04 (m, 1H), 5.88 (s, 1H), 7.62 (t, 1H, J ) 7.6 Hz),
7.70 (t, 1H, J ) 7.6 Hz), 7.82 (d, 1H, J ) 7.3 Hz), 8.03 (d, 1H,
J ) 7.3 Hz). 13C NMR δ: 19.1, 20.8, 28.1, 28.5, 56.5, 73.9, 78.4,
108.6, 125.4, 128.6, 131.4, 132.0, 142.0, 144.4, 153.5, 170.5.
IR 1732, 1597, 1061. MS m/z (%): 354 (M+, 2.0), 156 (34), 85
(100). HRMS calcd for C16H18O5S2: 354.0596. Found: 354.0597.
(1S,5S)-3-[[(1S,6R)-6-(Ben zyloxy)-3-cycloh exen -1-yl]oxy]-
4H-1,5-ben zod ith iep in e 1,5-Dioxid e (8c). Yield: 85% (color-
give 7f (152 mg, 89%, 1:1 mixture of amide bond rotamers) as
1
a colorless oil. [R]32 -135.6 (c 0.89, CHCl3). H NMR δ: 3.04
D
(d, 1H, J ) 14.0 Hz), 3.22-3.25 (m, 2H), 3.33 (dd, 1H, J )

C2-Symmetric Bis-sulfoxide
J . Org. Chem., Vol. 65, No. 11, 2000 3291
1
less oil). [R]25 +74.3 (c 0.88, CHCl3). H NMR δ: 2.25-2.46
(s, 1H), 7.24-7.35 (m, 10H), 7.65-7.69 (m, 2H), 7.89-7.94
(m, 2H). 13C NMR δ: 47.7 (1/2C), 48.0 (1/2C), 48.1 (1/2C), 48.5
(1/2C), 54.9 (1/2C), 55.1 (1/2C), 67.2, 72.4 (1/2C), 72.5 (1/2C),
75.2 (1/2C), 76.02 (1/2C), 77.2, 111.0 (1/2C), 111.7 (1/2C), 125.0
(1/2C), 125.1 (1/2C), 127.8, 128.0, 128.1, 128.2, 128.5 (3C),
128.6 (3C), 129.0, 131.66 (1/2C), 131.74 (1/2C), 131.8 (1/2C),
132.0 (1/2C), 136.3 (1/2C), 136.9 (1/2C), 140.4, 145.4 (1/2C),
145.9 (1/2C), 150.7 (1/2C), 151.4 (1/2C), 154.5 (1/2C), 154.6
(1/2C), 178.6. IR 1705, 1603, 1061. MS (FAB) m/z: 538 (M +
H)+. HRMS (FAB) calcd for C28H27O6S2 + H+: 538.1358.
Found: 538.1380.
D
(m, 4H), 3.77-3.79 (m, 1H), 4.06 (d, 1H, J ) 15.9 Hz), 4.23 (d,
1H, J ) 15.9 Hz), 4.37-4.39 (m, 1H), 4.51 (d, 1H, J ) 12.2
Hz), 4.60 (d, 1H, J ) 12.7 Hz), 5.49-5.51 (m, 1H), 5.59-5.61
(m, 1H), 5.84 (s, 1H), 7.23-7.32 (m, 5H), 7.62-7.70 (m, 2H),
7.86 (d, 1H, J ) 7.3 Hz), 7.97 (d, 1H, J ) 7.9 Hz). 13C NMR δ:
28.0, 28.7, 56.6, 71.3, 73.3, 75.5, 110.0, 122.9, 124.4, 125.3,
127.7 (2C), 127.9, 128.5 (2C), 129.1, 131.7, 131.9, 138.3, 141.8,
145.0, 152.8. IR 1597, 1059. MS (FAB) m/z: 415 (M + H)+.
HRMS (FAB) calcd for C22H22O4S2 + H+: 415.1036. Found:
415.1044.
(1R,5R)-3-[[(1R,2S)-2-(Acetoxy)-5-cycloocten -1-yl]oxy]-
4H-1,5-ben zod ith iep in e 1,5-Dioxid e (8d ). Yield: 90% (color-
(1S,6R)-6-(Ben zyloxy)-3-cycloh exen -1-ol (9). A drop of
10% HCl was added to a solution of 8d (493 mg, 1.19 mmol)
in acetone (12.0 mL) with stirring at rt. The stirring was
continued for 20 min. The reaction was quenched with
saturated NaHCO3, and the mixture was extracted with
AcOEt. The extract was washed with saturated NaHCO3 and
brine prior to drying and solvent evaporation. The crude was
chromatographed on silica gel with hexane-AcOEt (1:3) to
give 9 (240 mg, 99%) as a colorless oil along with (S,S)-1 (220
less oil). [R]23 -9.8 (c 0.65, CHCl3). 1H NMR δ: 1.64-1.69
D
(m, 1H), 1.72-1.78 (m, 1H), 1.90-1.98 (m, 4H), 2.05 (s, 3H),
2.50-2.51 (m, 2H), 4.16 (d, 1H, J ) 15.3 Hz), 4.28 (d, 1H, J )
15.3 Hz), 4.39 (dd, 1H, J ) 7.0, 4.0 Hz), 5.16 (dd, 1H, J ) 8.5,
3.7 Hz), 5.70-5.72 (m, 2H), 5.83 (s, 1H), 7.65 (dt, 1H, J ) 7.3,
1.4 Hz), 7.69 (dt, 1H, J ) 7.3, 1.4 Hz), 7.91 (dd, 1H, J ) 7.3,
1.2 Hz), 7.97 (dd, 1H, J ) 7.3, 1.2 Hz). 13C NMR δ: 21.5, 23.1,
23.6, 28.3, 29.5, 56.1, 74.8, 77.2, 110.7, 125.2, 129.3, 129.8,
130.2, 131.6, 131.8, 141.4, 145.1, 152.0, 170.0. IR 1736, 1606,
1059. MS m/z (%): 394 (M+, 2.8), 378 (3.5), 107 (100), 79 (97).
HRMS calcd for C19H22O5S2: 394.0908. Found: 394.0885.
(1R,5R)-3-[[(3R,4S)-4-(Ben zyloxy)t et r a h yd r op yr a n -3-
yl]oxy]-4H-1,5-ben zod ith iep in e 1,5-Dioxid e (8e). Yield:
71% (yellow oil). [R]30D -21.2 (c 0.44, CHCl3). 1H NMR δ: 3.76
(dd, 1H, J ) 9.2, 6.19 Hz), 3.81 (dd, 1H, J ) 10.4, 3.7 Hz),
3.93 (dd, 1H, J ) 9.2, 6.1 Hz), 3.99 (dd, 1H, J ) 9.8, 5.2 Hz),
4.09 (d, 1H, J ) 16.5 Hz), 4.12-4.17 (m, 1H), 4.24 (d, 1H, J )
16.5 Hz), 4.46-4.52 (m, 3H), 5.72 (s, 1H), 7.24-7.33 (m, 5H),
7.65-7.69 (m, 2H), 7.92-7.94 (m, 2H). 13C NMR δ: 55.1, 70.0,
70.2, 72.8, 76.2, 76.7, 110.8, 125.0, 127.8 (2C), 128.1, 128.5
(2C), 128.7, 131.7, 131.9, 137.0, 140.8, 145.5, 151.8. IR 1599,
1059. MS (FAB) m/z: 405 (M + H)+. HRMS (FAB) calcd for
mg, 81%) as a colorless powder. [R]27 -24.1 (c 1.13, CHCl3).
D
1H NMR δ: 2.16 (d, 1H, J ) 4.9 Hz), 2.32-2.34 (m, 4H), 3.67-
3.70 (m, 1H), 4.09-4.12 (m, 1H), 4.58 (d, 3H, J ) 12.2 Hz),
4.65 (d, 3H, J ) 12.2 Hz), 5.56-5.61 (m, 2H), 7.29-7.38 (m,
5H). 13C NMR δ: 27.2, 31.6, 66.7, 70.3, 75.9, 123.6, 123.8,
127.6, 127.7, 128.4, 138.4. IR 3450. MS m/z (%): 204 (M+, 16.5),
91 (100). Anal. Calcd for C13H16O2: C, 76.44; H, 7.89. Found:
C, 76.26; H, 7.90.
Ack n ow led gm en t. We thank Professor J . D. Martin
(Sevilla University) for provision of us the procedure of
6c and also appreciate the Grant-in-Aid for Encourage-
ment of Young Scientists from the Ministry of Educa-
tion, Science and Culture (No. 06772071).
C
20H20O5S2 + H+: 405.0830. Found: 405.0828.
(1S,5S)-3-[[(3S,4R)-4-(Ben zyloxy)-1-(Ben zyloxyca r bon -
Su p p or tin g In for m a tion Ava ila ble: The data (1H, 13C,
IR, and MS) for 4a , 4b, (S)-5, (S,S)-1, 7c, and 8c and structural
determination summaries and tables of X-ray structural data
for 4a , (R,R)-1, and (()-7c. This material is available free of
charge via the Internet at http://pubs.acs.org.
yl)p yr r olid in e-3-yl]oxy]-4H-1,5-ben zod ith iep in e 1,5-Di-
oxid e (8f). Yield: 84% (colorless oil, 1:1 mixture of amide bond
1
rotamers). [R]29 +12.2 (c 1.2, CHCl3). H NMR δ: 3.40-3.67
D
(m, 4H), 4.05 (d, 1H, J ) 16.5 Hz), 4.08-4.11 (m, 1H), 4.19 (d,
1H, J ) 16.5 Hz), 4.44-4.48 (m, 2H), 4.55 (t, 1H, J ) 11.3
Hz), 5.06 (d, 1H, J ) 12.2 Hz), 5.11 (d, 1H, J ) 12.2 Hz), 5.72
J O9919409