Stereochemical research on the hydrolysis of optically pure spirosulfuranes: Efficient synthesis of chiral sulfoxides with completely opposite stereochemistry

Article abstract of DOI:10.1021/jo981330t

The synthesis of optically pure alkoxy(acyloxy)spirosulfuranes 5a-e, using the 2-exo-hydroxy-10-bornyl group as a chiral ligand, has been developed in high yield and with excellent diastereo-selectivity. The X-ray analyses of 5a and 5b indicated that the spirosulfuranes have the trigonal bipyramidal (TBP) structures around the sulfur atom. Recrystallization of 5c,d from moist solvent (95% EtOH aq) gave sulfoxides 7c,d, respectively, as single products with an S(s) absolute configuration at the sulfur atom. In contrast, hydrolysis of sulfuranes 5b,c,d under the basic conditions afforded the sulfoxides 8b,c,d, with an R(s) absolute configuration at the sulfur atom, in high yield and with excellent diastereoselectivity. The stereochemical and mechanistic study of the hydrolysis of spirosulfuranes was performed by using spirosulfurane 5a. Hydrolysis of 5a under acidic and basic conditions gave, diastereoselectively, the corresponding sulfoxides 7a and 8a with the opposite absolute configuration at the sulfur atom. The structures of the sulfoxides 7a,c and 8a,b were confirmed by X-ray crystallographic analyses. The mass spectral and ¹⁷O NMR studies of the sulfoxides 7a- (18(17))O and 8a-(18(17))O, which were prepared by the hydrolysis of 5a with isotopically labeled water, revealed definitely that the oxygen atom bound to the sulfur atom in these compounds derives from water. The possible mechanisms of the reactions which account for the observed stereochemical results have been suggested.

Full text of DOI:10.1021/jo981330t

J . Org. Chem. 1998, 63, 9375-9384
9375
Ster eoch em ica l Resea r ch on th e Hyd r olysis of Op tica lly P u r e
Sp ir osu lfu r a n es: Efficien t Syn th esis of Ch ir a l Su lfoxid es w ith
Com p letely Op p osite Ster eoch em istr y
J ian Zhang,*,† Shinichi Saito, and Toru Koizumi*,‡
Faculty of Pharmaceutical Sciences, Toyama Medical & Pharmaceutical University,
2630 Sugitani, Toyama 930-01, J apan
Received J uly 8, 1998
The synthesis of optically pure alkoxy(acyloxy)spirosulfuranes 5a -e, using the 2-exo-hydroxy-10-
bornyl group as a chiral ligand, has been developed in high yield and with excellent diastereo-
selectivity. The X-ray analyses of 5a and 5b indicated that the spirosulfuranes have the trigonal
bipyramidal (TBP) structures around the sulfur atom. Recrystallization of 5c,d from moist solvent
(95% EtOH aq) gave sulfoxides 7c,d , respectively, as single products with an SS absolute
configuration at the sulfur atom. In contrast, hydrolysis of sulfuranes 5b,c,d under the basic
conditions afforded the sulfoxides 8b,c,d , with an RS absolute configuration at the sulfur atom, in
high yield and with excellent diastereoselectivity. The stereochemical and mechanistic study of
the hydrolysis of spirosulfuranes was performed by using spirosulfurane 5a . Hydrolysis of 5a under
acidic and basic conditions gave, diastereoselectively, the corresponding sulfoxides 7a and 8a with
the opposite absolute configuration at the sulfur atom. The structures of the sulfoxides 7a ,c and
8a ,b were confirmed by X-ray crystallographic analyses. The mass spectral and 17O NMR studies
of the sulfoxides 7a -18(17)O and 8a -18(17)O, which were prepared by the hydrolysis of 5a with
isotopically labeled water, revealed definitely that the oxygen atom bound to the sulfur atom in
these compounds derives from water. The possible mechanisms of the reactions which account for
the observed stereochemical results have been suggested.
In tr od u ction
the intermediates or transition states in various reactions
involving chalcogenium compounds, such as Swern oxi-
dation and Pummerer rearrangement.3 Recently, some
groups have proposed that the formation of chalco-
genurane species is the key step in the biomimic reactions
of some enzymes.4 Therefore, the synthesis and isolation
of chiral chalcogenuranes are apparently important to
investigate the stereochemistry of their reactions as well
as the roles in the biomimic reactions.
Since the first synthesis of the chiral chlorosulfurane
1 reported by Martin 20 years ago,5 a number of chiral
spirosulfuranes have been synthesized or isolated (Scheme
1).6 Kapovits et al. have reported the synthesis of both
(+)- and (-)-sulfuranes 2a via the reaction of correspond-
ing optically active (+)- and (-)-sulfoxides with acetyl
chloride in the presence of triethylamine.6a,e Isolation of
Although the stereochemical and mechanistic research
on the nucleophilic reaction of compounds at a tetra-
coordinated atom, such as carbon, has been widely
studied and an SN1 or SN2 pathway has been accepted
as the general concept of organic reactions, the research
on that of the pentacoordinated atom is quite limited to
some silicon and phosphorus compounds.1 Chalco-
genuranes, are a kind of pentacoordinated (including the
equatorial lone pair electrons) hypervalent compounds,
usually with a trigonal bipyramidal (TBP) geometry.2
Thus, a stereochemical study of the reaction of chalco-
genuranes would lead to a general comprehension of the
reactions that occur at the pentacoordinated or the
multicoordinated heteroatom-containing compounds. On
the other hand, chalcogenuranes have been proposed as
(3) Recent reviews on the reactions concerning the formation of
chalcogenuranes as intermediates: (a) Mancuso, A. J .; Swern, D.
Synthesis 1981, 164-185. (b) Tidwell, T. T. Synthesis 1990, 857-870.
(c) Oae, S.; Uchida, Y. Acc. Chem. Res. 1991, 24, 202-208. (d) Kita, Y.
Phosphorus, Sulfur Silicon 1997, 120 and 121, 145-164. (e) Ka-
washima, T.; Okazaki, R. Synlett 1996, 600-608.
† Present address: Department of Life and Environmental Sciences,
Graduate School of Arts and Sciences, The University of Tokyo,
Komaba 3-8-1, Meguro, Tokyo 153-8902, J apan. e-mail: zhang@
selen.c.u-tokyo.ac.jp.
‡ Deceased, J anuary 12, 1998.
(4) (a) House, K. L.; Dunlap, R. B.; Odom, J . D.; Wu, Z.-P.; Hilvert,
D. J . Am. Chem. Soc. 1992, 114, 8573-8579. (b) Engman, L.; Stern,
D.; Cotgreave, I. A.; Andersson, C. M. J . Am. Chem. Soc. 1992, 114,
9737-9743. (c) Engman, L.; Stern, D.; Pelcman, M.; Andersson, C. M.
J . Org. Chem. 1994, 59, 1973-1979. (d) Detty, M. R.; Friedman, A.
E.; Oseroff, A. R. J . Org. Chem. 1994, 59, 8245-8250. (e) Iwaoka, M.;
Tomoda, S. J . Am. Chem. Soc. 1994, 116, 2557-2561. (f) Vessman,
K.; Ekstro¨m, M.; Berglund, M.; Andersson, C. M.; Engman, L. J . Org.
Chem. 1995, 60, 4461-4467. (g) Mohsine, A.; Christiaens, L. Hetero-
cycles 1996, 43, 2567-2593. (h) Back, T. G.; Dyck, B. P, J . Am. Chem.
Soc. 1997, 119, 2079-2083. (i) Fong, M. C.; Schiesser, C. H. J . Org.
Chem. 1997, 62, 3103-3108. (j) Detty, M. R.; Zhou, F.; Friedman, A.
E. J . Am. Chem. Soc. 1996, 118, 313-318. (k) Albeck, A.; Weitman,
H.; Sredni, B.; Albeck, M. Inorg. Chem. 1998, 37, 1704-1712.
(5) (a) Balthazor, T. M.; Martin, J . C. J . Am. Chem. Soc. 1975, 97,
5634-5635. (b) Martin, J . C.; Balthazor, T. M. J . Am. Chem. Soc. 1977,
99, 152-162.
(1) Reviews on the reactions of the pentacoordinated silicon and
phosphorus compounds: (a) Holmes, R. R. Acc. Chem. Res. 1972, 5,
296-303. (b) Holmes, R. R. Acc. Chem. Res. 1979, 12, 257-265. (c)
Chuit, C.; Corriu, R. J . P.; Reye, C.; Young, J . C. Chem. Rev. 1993, 93,
1371-1448. (d) Dillon, K. B. Chem. Rev. 1994, 94, 1441-1456. (e)
Holmes, R. R. Chem. Rev. 1996, 96, 927-950. Recent example: (f)
Chang, N.; Lim, C. J . Am. Chem. Soc. 1998, 120, 2156-2167. (g) Kubo,
K.; Nakazawa, H.; Kawamura, K.; Mizuta, T.; Miyoshi, K. J . Am.
Chem. Soc. 1998, 120, 6715-6727.
(2) Reviews on the chemistry of chalcogenuranes: (a) Martin, J . C.;
Paul, I. C. Science 1976, 191, 154-159. (b) Martin, J . C. Science 1983,
221, 509-514. (c) Hayes, R. A.; Martin, J . C. In Organic Sulfur
Chemistry, Theoretical and Experimental Advances; Bernardi, F.,
Csizmadia, I. G., Mangini, A., Eds.; Elsevier: Amsterdam, 1985; pp
408-483. (d) Oae, S. Organic Sulfur Chemistry: Structure and
Mechanism; CRC Press: Boca Raton, FL, 1991.
10.1021/jo981330t CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/19/1998

9376 J . Org. Chem., Vol. 63, No. 25, 1998
Zhang et al.
Sch em e 1
of the reaction of hypervalent chalcogenium compounds
and to seek efficient methods to synthesize the chiral
chalcogenonium(IV) compounds, we designed and pre-
pared the chiral spirosulfuranes 5a -e, using the 2-exo-
hydroxy-10-bornyl group as a chiral ligand, with two
different kinds of oxygen atoms (alkoxy and acyloxy)
bound to the central sulfur atom. We hoped the difference
of these two oxygen groups at the apical positions of the
trigonal bipyramidal (TBP) structure of spirosulfuranes
5 would display a difference of reactivity under various
conditions and, therefore, affect the stereochemical pro-
cess of the nucleophilic reactions of the spirosulfuranes
which might in turn afford products with different
stereochemistry around the central sulfur atom. Herein
we report our results on the synthesis, structure, and
mechanistic research on the hydrolysis of these chiral
spirosulfuranes.9
optically pure spirosulfurane 2b has been successfully
carried out by Allenmark et al. by using chiral HPLC.6b
Recently, Martin and co-workers have reported their
synthesis of optically active spirosulfuranes 2c,d via the
reaction of sulfoxides with chiral acid.6c,d However, there
is only one report on the synthesis of optically active
spirosulfuranes with definite determination of the
structure.6e And, to the best of our knowledge, up to now
there is no example of the stereochemical aspects of the
nucleophilic reaction of a chiral spirosulfurane.
Our group has carried out the synthesis, reaction, and
stereochemical research on chiral hypervalent chalcoge-
nium compounds by using the 2-exo-hydroxy-10-bornyl
group as a chiral auxiliary.7 We found it is a good ligand
for the stereoselective synthesis of optically pure chal-
cogenuranes 3. Using this ligand, we have synthesized
the chiral halooxasulfuranes 3a ,7e selenuranes 3b,7a and
telluranes 3c7d in very high yields and with excellent
diastereoselectivities (Scheme 1). The bornyl group has
proved to be an excellent group for the diastereoselective
synthesis of these compounds; its bulky protective factor
as well as the five-numbered ring effect have been
considered as the main reasons for the stability of these
compounds and the diastereoselectivity of their synthesis.
Hydrolysis of chiral chlorosulfuranes 3a (X ) Cl) as well
as other nucleophilic reactions of halooxachalcogenuranes
3 afforded a good method to prepare the optically pure
chalcogenonium(IV) compounds.7 On the other hand, our
laboratory, as well as some other groups, have confirmed
that these optically pure chalcogenonium(IV) compounds
are very useful chiral blocks in the synthesis of some
optically active natural products through the asymmetric
Diels-Alder reaction,8a-c [2,3]sigmatropic rearrange-
ment,7c,f,g etc.8d,e To gain insight into the stereochemistry
Resu lts a n d Discu ssion
Syn th esis a n d Ster eoch em istr y of Op tica lly P u r e
Sp ir osu lfu r a n es 5a -e. Synthesis of optically pure
spirosulfuranes 5a -e with 2-exo-hydroxy-10-bornyl group
as a chiral ligand is shown in Scheme 2. Reaction of chiral
sulfides 4a -e, which were readily prepared from (1S)-
(-)-10-iodo-2-exo-bornanol7j or (-)-10-mercaptoisoborneol,
with t-BuOCl (1.1 equiv) at 0 °C for 30 min in anhydrous
dichloromethane under nitrogen followed by treatment
with Et3N (1.2 equiv) for 1.5 h gave optically pure
spirosulfuranes 5a -e in high yield and as single dia-
stereomers; no any other epimeric compounds could be
detected.10 The reactions are believed to proceed through
the diastereoselective generation of intermediates of
chlorosulfuranes 6, which had been proposed previously,
followed by intramolecular cyclization.
Sch em e 2
(6) On the synthesis and isolation of chiral spirosulfuranes: (a)
Huszthy, P.; Kapovits, I.; Kucsman, AÄ .; Radics, L. Tetrahedron Lett.
1978, 1853-1856. (b) Allenmark, S.; Claeson, S. Tetrahedron: Asym-
metry 1993, 4, 2329-2332. (c) Drabowicz, J .; Martin, J . C. Tetrahe-
dron: Asymmetry 1993, 4, 297-300. (d) Drabowicz, J .; Martin, J . C.
Pure Appl. Chem. 1996, 68, 951-956. (e) Szabo´, D.; Szendeffy, S.;
Kapovits, I.; Kucsman, AÄ .; Czugler, M.; Ka´lma´n, A.; Nagy, P. Tetra-
hedron: Asymmetry 1997, 8, 2411-2420.
(7) (a) Takahashi, T.; Kurose, N.; Kawanami, S.; Arai, Y.; Koizumi,
T.; Shiro, M. J . Org. Chem. 1994, 59, 3262-3264. (b) Takahashi, T.;
Kurose, N.; Kawanami, S.; Nojiro, A.; Arai, Y.; Koizumi, T.; Shiro, M.
Chem. Lett. 1995, 379-380. (c) Kurose, N.; Takahashi, T.; Koizumi,
T. J . Org. Chem. 1996, 61, 2932-2933. (d) Takahashi, T.; Zhang, J .;
Kurose, N.; Takahashi, S.; Koizumi, T.; Shiro, M. Tetrahedron:
Asymmetry 1996, 7, 2797-2800. (e) Zhang, J .; Takahashi, T.; Koizumi,
T. Heterocycles 1997, 44, 325-339. (f) Kurose, N.; Takahashi, T.;
Koizumi, T. J . Org. Chem. 1997, 62, 4562-4563. (g) Kurose, N.;
Takahashi, T.; Koizumi, T. Tetrahedron 1997, 53, 12115-12129. (h)
Zhang, J .; Saito, S.; Koizumi, T. Tetrahedron: Asymmetry 1997, 8,
3357-3361. (i) Zhang, J .; Saito, S.; Koizumi, T. J . Org. Chem. 1998,
63, 5265-5267. (j) Zhang, J .; Saito, S.; Koizumi, T. J . Org. Chem. 1998,
63, 5423-5429.
(8) (a) Koizumi, T. Phosphorus, Sulfur Silicon 1991, 58, 111-127.
(b) Arai, Y. Koizumi, T. Sulfur Rep. 1993, 15, 41-65. (c) Aversa, M.
C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.; Panzalorto, M.; Rizzo,
S. Tetrahedron: Asymmetry 1998, 9, 1577-1588, and references
therein. (d) Takahashi, T.; Nakao, N.; Koizumi, T. Chem. Lett. 1996,
207-208. (e) Takahashi, T.; Nakao, N.; Koizumi, T. Tetrahedron:
Asymmetry 1997, 8, 3293-3308.
(9) Preliminary communication of this work: Zhang, J .; Saito, S.;
Koizumi, T. J . Am. Chem. Soc. 1998, 120, 1631-1632.
(10) See Experimental Section for detailed procedures. Sulfurane
5e is not stable to moisture, and only the sulfoxide was obtained after
extraction with EtOAc from water. The structure of sulfurane 5e was
determined by the 1H NMR analysis of the crude product which was
directly evaporated without extraction.

Hydrolysis of Optically Pure Spirosulfuranes
J . Org. Chem., Vol. 63, No. 25, 1998 9377
The formation of the five-membered spirosulfurane
structure was detected by spectroscopic means. In the
1H NMR spectra of spirosulfuranes, the chemical shifts
of protons on the methylene bound to the sulfur atom
are considerably downfield as compared with those of the
analogous sulfides and sulfoxides. In the 13C NMR
spectra, the chemical shift of the carbon bound to the
alkoxy oxygen in spirosulfuranes 5a -d is at about 95
ppm whereas shifts of the corresponding carbon atom of
sulfides and sulfoxides are at about 77 ppm. These
spectral characteristic could be considered as the features
of compounds with TBP structure.7 On the other hand,
sulfuranes 5a -d have their carbonyl stretching frequen-
cies at 1657-1664 cm-1, which are considerably lower
as compared with those of general carbonyl groups.
Previous study on the relationship between the struc-
tures and the carbonyl stretching frequencies of spiro-
sulfuranes indicated that the lower carbonyl stretching
frequency could been considered as an indication of a high
degree of carboxylate anion character in carbonyl-
containing spirosulfuranes.11,12c,13c The acyloxy ligand is
effectively more electronegative than the alkoxy ligand,
and electron density is expected to be removed from the
alkoxy ligand toward the acyloxy ligand. Thus, these two
S-O bonds at the apical positions of the sulfuranes were
expected to show different structural and reactive prop-
erties.
equatorial positions, while the two electronegative oxygen
atoms bound to the sulfur atom occupy apical positions.
The O-S-O moieties with the angle of 177.1° and 178.9°
in 5a and 5b, respectively, are almost linear. Systemic
investigation on the crystallographic structures of some
achiral spirosulfuranes has indicated that there is some
characteristic relationship between the sum of the O-S-O
distances, as well as the S-O distances, and the structure
of the spirosulfuranes.12 Thus, the sum of the S-O-S
distances in bis(acyloxy)spirosulfuranes are longer than
those in dialkoxy analogues but shorter than in the mixed
alkoxy(acyloxy) derivatives, and the length of S-O(alkoxy)
is usually shorter than that of the S-O(acyloxy) in the
alkoxy(acyloxy)spirosulfurane. Our X-ray analyses gave
a similar result: the sum of the O-S-O bond distances
in 5a and 5b [3.759(3) and 3.765(6) Å, respectively] is
consistent with those of racemic alkoxy(acyloxy)spirosul-
furanes, the bond length of the S-O (alkoxy) [1.686(6)
and 1.650(3) Å for 5a and 5b, respectively] is shorter than
that of the S-O (acyloxy) [2.072(7) and 2.115(3) Å for 5a
and 5b, respectively], which shows a “alkoxy-sulfonium-
carboxylate zwitterion characteristic” as do the racemic
spirosulfuranes.12 The different structural properties of
the two oxygen groups at the apical positions were
expected to lead to a difference in the reactivity of
spirosulfuranes under various conditions.
Ster eoch em ica l a n d Mech a n istic Resea r ch on th e
Hyd r olysis of Sp ir osu lfu r a n es. Spirosulfuranes 5a
and 5b are stable, and no hydrolysis or isomerizations
were observed at room temperature for several days.
Refluxing a solution of spirosulfuranes 5a in anhydrous
EtOH or in EtOH-H2O (95:5) for 5 h gave only the
recovery of the starting material (Table 1). Compared to
5a , the sulfuranes 5c,d are not too stable to moisture.
Recrystallization of 5c,d from moist solvent (EtOH, 95%
aq) gave the products of the hydrolysis, sulfoxides 7c,d ,
as single diastereomers in high yields. The stereochem-
istry of 7c,d has been determined by an X-ray analysis
of 7c which indicated that the absolute configuration of
the sulfur atom is SS as shown in Figure 2.
Ta ble 1. Th e Hyd r olysis of 5a u n d er Ba sic or Acid ic
Con d ition s
entry substrate
condition
product yield (%)
1
2
3
4
5
6
5a
5a
5a
5a
5a
5a
EtOH, reflux, 5 h
EtOH-H2O, reflux, 5 h 5a
1 N HCl, rt, 48 h
1 N NaOH, 0 °C, 0.5 h
1 N HCl, reflux, 5 h
1 N NaOH, reflux, 5 h
5a
99
99
98
88
7a
8a
F igu r e 1. ORTEP drawing of the compounds 5a and 5b with
50% thermal ellipsoids.
7a + 8a 87 (2:1)a
8a
90
a
The X-ray crystallographic analyses of 5a and 5b
indicate that the spirosulfuranes have slightly distorted
trigonal bipyramidal (TBP) structures as shown in Figure
1. As expected, two carbon atoms and a lone pair occupy
Ratio in parentheses refers to 7a :8a .
Previous study of the hydrolysis of racemic spirosul-
furanes showed that these compounds are readily hy-
drolyzed to their parent sulfoxides and that their stability
decreased with increasing electron density at the sulfur
atom and with enlarging the size of the spiro rings from
five- to six-membered.13 However, since these spirosul-
furanes are achiral or racemic, the stereochemistry of the
reactions was unclear. On the other hand, oxidation of
the 2-exo-hydroxy-10-bornyl sulfides with t-BuOCl7e or
MCPBA14 has been extensively studied. The hydroxyl
group has been known to play a key role in the control
of the diastereoselectivity through the formation of
intermediate chlorosulfuranes, or through hydrogen bond-
ing with the oxidative reagent (MCPBA). Thus, hydroly-
(11) Livant, P.; Martin, J . C. J . Am. Chem. Soc. 1977, 99, 5761-
5767.
(12) (a) Adzima, L. J .; Martin, J . C. J . Org. Chem. 1977, 42, 4006-
4016. (b) Kapovits, I.; Ra´bai, J .; Szabo´, D.; Czako´, K.; Kucsman, AÄ .;
Argay, G.; Fu¨lo¨p, V.; Ka´lma´n, A.; Koritsa´nszky, T.; Pa´rka´nyi, L. J .
Chem. Soc., Perkin Trans. 2 1993, 847-853. (c) Hornbuckle, S. F.;
Livant, P.; Webb, T. R. J . Org. Chem. 1995, 60, 4153-4159. (d) Szabo´,
D.; Kapovits, I.; Argay, G.; Czugler, M.; Ka´lma´n, A.; Koritsa´nszky, T.
J . Chem. Soc., Perkin Trans. 2 1997, 1045-1053.
(13) (a) Lam, W. Y.; Duesler, E. N.; Martin, J . C. J . Am Chem. Soc.
1981, 103, 127-135. (b) Vass, E.; Ruff, F.; Kapovits, I.; Ra´bai, J .; Szabo´,
D. J . Chem. Soc., Perkin Trans. 2 1993, 855-859. (c) Vass, E.; Ruff,
F.; Kapovits, I.; Szabo´, D.; Kucsman, AÄ . J . Chem. Soc., Perkin Trans.
2 1997, 2061-2068. (d) AÄ da´m, T.; Ruff, F.; Kapovits, I.; Szabo´, D.;
Kucsman, AÄ . J . Chem. Soc., Perkin Trans. 2 1998, 1269-1275.

9378 J . Org. Chem., Vol. 63, No. 25, 1998
Zhang et al.
sis of chlorosulfuranes or the oxidation of the sulfides
with MCPBA has been known to give sulfoxides with a
predictable absolute configuration at sulfur atom. Inter-
estingly, the sulfoxides 7c,d are of the opposite absolute
configuration at the sulfur atom as compared with that
of sulfoxides obtained by the usual oxidation.
Sch em e 3
F igu r e 2. ORTEP drawing of the compounds 7c and 8b with
50% thermal ellipsoids.
Sch em e 4
These fascinating results prompted us to investigate
the basic hydrolysis of spirosulfuranes 5c,d . Hydrolysis
of 5c,d with 1 N aq NaOH at 0 °C for 0.5 h afforded the
sulfoxides 8c,d in high yield and with excellent diaste-
reoselectivity. Since the spectral characteristics of the
sulfoxides 7c,d and the corresponding 8c,d , obtained
through the basic hydrolysis, were quite different, the
latter appeared to be the diastereomers of the former at
the sulfur atom, respectively.15 An X-ray analysis of the
sulfoxide 8b, obtained by a similar basic hydrolysis of
spirosulfurane 5b, proved that the above suggestion of
the stereochemistry of the sulfoxides 8c,d is correct
(Figure 2). Our initial results mentioned above indicated
that the structure of the spirosulfuranes, especially the
two apical S-O bonds, might play an important role in
the control of the stereochemistry of the hydrolysis of
these hypervalent sulfur compounds depending the con-
ditions used.
solution, 5a recovered without an appreciable change;
however, hydrolysis of spirosulfuranes 5a in a solution
of EtOH with 1 N aq HCl at room temperature for 48 h
gave sulfoxide 7a in high yield as a single diastereomer.
The SS absolute configuration of the sulfur atom in
sulfoxide 7a has been determined by an X-ray analysis
as shown in Figure 3. On the contrary, stirring an EtOH
To gain a deeper understanding of the reactions of
these spirosulfuranes, we carried out the hydrolysis of
the spirosulfurane 5a , which is comparatively stable,
under various conditions to see how the conditions affect
the diastereoselectivity of the reactions (Scheme 4, Table
1). As mentioned above, even by refluxing an EtOH-H2O
(14) (a) Lucchi, O. D.; Lucchini, V.; Marchioro, L.; Valle, G.; Modena,
G. J . Org. Chem. 1986, 51, 1457-1466. Lucchi, O. D.; Lucchini, V.;
Marchioro, L.; Valle, G.; Modena, G. J . Org. Chem. 1989, 54, 3245. (b)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Farina, S.; Montanari, V.
Tetrahedron 1987, 43, 1013-1018. (c) Eschler, B. M.; Haynes, R. K.;
Kremmydas, S.; Ridley, D. D. J . Chem. Soc., Chem. Commun. 1988,
137-138. (d) Hung, S. M.; Lee, D. S.; Yang, T. K. Tetrahedron:
Asymmetry 1990, 1, 873-876. (e) Arai, Y.; Matsui, M.; Koizumi, T.
Synthesis 1990, 320-323. (f) Eschler, B. M.; Haynes, R. K.; Ironside,
M. D.; Kremmydas, S.; Ridley, D. D.; Hambley, T. W. J . Org. Chem.
1991, 56, 4760-4766.
(15) To confirm the stereochemistry of 8c,d , hydrolysis of chloro-
sulfuranes 6c,d under basic condition has been performed to give
sulfoxides in high yield and diastereoselectivity. The spectral data of
the products are identical with that of sulfoxides 8c,d , which indicated
definitely that the stereochemistry of the sulfoxides are as shown in
Scheme 3.
F igu r e 3. ORTEP drawing of the compounds 7a and 8a with
50% thermal ellipsoids.

Hydrolysis of Optically Pure Spirosulfuranes
J . Org. Chem., Vol. 63, No. 25, 1998 9379
Sch em e 5
solution of 5a in a 1 N aq NaOH at 0 °C for 0.5 h gave
optically pure sulfoxide 8a in 88% yield, also as a single
diastereomer but with an opposite absolute configuration
at the sulfur atom. The stereochemistry of sulfoxide 8a
has also been clearly determined by an X-ray analysis
as shown in Figure 3.
Although we believe that the stereochemical outcome
results from the diastereoselective hydrolysis of the
sulfurane 5a , the isomerization of the products should
be investigated to verify the optically stability of the
sulfoxides. The chiral chalcogenonium(IV) compounds
have been known to isomerize through the pyramidal
inversion or the formation of pentacoordinated interme-
diates.16 Isomerization of sulfoxides 7a and 8a under
various conditions has been, therefore, studied to clarify
the optically stability of them. As shown in Table 2, no
isomerization could been observed after stirring 7a and
8a in 1 N NaOH-EtOH solution at room temperature
or under reflux for a considerably long time. Stirring 7a
and 8a in 1 N HCl-EtOH solution at room temperature
for 48 h resulted in only their recovery. Only a slight
isomerization was really observed even after refluxing
7a and 8a in 1 N HCl-EtOH solution for 5 h, respec-
tively. However, since the hydrolytic reactions of spiro-
sulfurane 5a were all performed under mild conditions,
the possibility of the isomerization of their products
during the hydrolysis could be ruled out. Therefore, we
can conclude that the excellent diastereoselectivity of
these reactions is induced from the difference of the
reactivity of the two S-O bonds of the spirosulfuranes.
with that of 9-16O (or 10-16O)].17 The position of the
oxygen atom from H2O was studied by use of 17O NMR.18
Since there should be a quite different chemical shift for
the oxygen bound to sulfur and the oxygen of the carbonyl
in the sulfoxides 7a and 8a , the 17O NMR spectra of these
compounds could provide important information on the
position of the oxygen from H2O. The products obtained
by hydrolysis of 5a with H217O under acidic and basic
conditions showed signals with chemical shift of -8.103
and -9.184 ppm in their 17O NMR spectra, respectively,
which indicated that the oxygen atoms from H2O were
definitely bound to the sulfur atoms of the products
(Scheme 4).
P ossible Mech a n ism s: Associa tion ver su s Dis-
socia tion . As compared with that of the tetracoordinated
atom, the stereochemistry of nucleophilic reactions oc-
curring at a pentacoordinated atom is more complex. Two
kinds of mechanisms, namely associative (analogous to
SN2-type reactions) and dissociative (analogous to SN1-
type reactions) mechanisms, have been suggested to
account for the nucleophilic reactions of the hypervalent
chalcogenium compounds.13,19 We have proposed an as-
sociative mechanism for the reaction of 5a as shown in
Scheme 6:9 hydrolysis under acidic and basic conditions
may proceed through the formation of the hexacoordi-
nated sulfur species B and D, which is generated,
respectively, from the attack of H2O onto the protonated
spirosulfurane A20 or the reaction of hydroxide anion with
5a . Since the protonated alkoxy group in B could be
considered a better leaving group as compared with the
acyloxy group bound to the same sulfur atom, the
cleavage of the S-O (alkoxy) bond followed by the
isomerization around the sulfur center generates the
pentacoordinated intermediate C with the hydroxy group
at the apical position.21 On the other hand, the S-O
(acyloxy) bond in D is easily broken as compared with
Ta ble 2. Th e Isom er iza tion of 7a a n d 8a u n d er Va r iou s
Con d ition s
entry substrate
conditiona
product
yield (%)
98
96
1
2
3
4
5
6
7
8
7a
7a
7a
7a
8a
8a
8a
8a
1 N HCl, rt, 48 h
1 N NaOH, rt, 48 h
1 N HCl, reflux, 5 h
1 N NaOH, reflux, 5 h 7a
1 N HCl, rt, 48 h
1 N NaOH, rt, 48 h
1 N HCl, reflux, 5 h
1 N NaOH, reflux, 5 h 8a
7a
7a
7a + 8a 96 (2.04:1)b
93
98
92
8a
8a
7a + 8a 92 (1:8.35)b
97
a
b
All reactions were carried out in the solution of EtOH. Ratio
in parentheses refers to 7a :8a .
To make the reaction mechanism clear, the mass and
17O NMR spectral studies of the products were performed
to see where H2O attacked and whether the oxygen bound
to the sulfur in the sulfoxides came from H2O or not.
Thus, the hydrolytic reactions of 5a under acidic and
basic conditions were carried out with H218O and H217O,
respectively (Scheme 4). Since no molecular peak could
be observed in the mass spectra of 7a and 8a , esterifi-
cation was necessary in order to observe the mass spectra
(Scheme 5). Hydrolysis of sulfurane 5a with H218O under
acidic and basic condition followed by esterification with
diazomethane gave the corresponding esters 9-18O and
10-18O in 98 and 91% yield, of which both mass spectra
have peaks at 339 (M+ + 1) (Scheme 5). The mass
spectroscopic analyses revealed that 9-18O and 10-18O are
enriched with 18O to a significant extent [91% and 70%
incorporation, respectively, which were obtained by
comparison of the mass spectrum of 9-18O (or 10-18O)
(17) The isotopic purity is calculated by comparing the height of
peaks at m/z ) 186 with that of peaks at m/z ) 184 in the mass spectra
of sulfoxides (7-18O or 8-18O), while in the mass spectra of sulfoxides
(7-16O or 8-16O) there are no peaks at m/z ) 186.
(18) Review on the 17O NMR: (a) Boykin, D. W.; Baumstark, A. L.
Tetrahedron 1989, 45, 3613-3651. On the chemical shift of sulfoxides
in 17O NMR spectroscope, see: (b) Dyer, J . C.; Harris, D. C.; Evans, J .
S. A. J . Org. Chem. 1982, 47, 3660-3664.
(16) (a) Shimizu, T.; Yoshida, M.; Kobayashi, M. Bull. Chem. Soc.,
J pn. 1987, 60, 1555-1557. (b) Shimizu, T.; Kobayashi, M.; Kamigata,
N. Bull. Chem. Soc., J pn. 1988, 61, 3761-3763. (c) Shimizu, T.;
Kamigata, N. J . Synth. Org. Chem., J pn. 1997, 55, 35-43.
(19) Twenty years ago, Martin et al. studied the mechanism of the
basic hydrolysis of chlorosulfuranes and proposed an associative
mechanism involving a hexacoordinated sulfur species with a negative
charge on sulfur, see: ref 5.

9380 J . Org. Chem., Vol. 63, No. 25, 1998
Zhang et al.
Sch em e 6
Sch em e 7
cation F affords sulfoxide with a SS absolute configura-
tion at the sulfur atom. While under a basic condition,
“alkoxy-sulfonium-carboxylate zwitterion character” of
the unsynmmetric spirosulfurane would lead the equi-
librium preferentially to the sulfonium cation G through
the cleavage of the S-O(acyloxy) bond,22 which then
induces the hydroxide ion to attack the sulfur atom from
the R-side to produce the sulfoxide with an RS configura-
tions at the sulfur atom. Therefore, the different stere-
ochemistry of the chiral sulfonium cation leads to the
diastereoselective generation of the sulfoxides with the
opposite absolute configuration at the sulfur atom.
Considering the numerous possible stereoisomers of a
hexacoordinated sulfur species in the associative pathway
(Scheme 6), it might be difficult to explain the high
diastereoselectivity of these reactions. Therefore, at
present, we consider the dissociative pathway more
reasonable.
S-O (alkoxy) bond, and the selective cleavage of the S-O
(acyloxy) bond and the isomerization around the sulfur
center produce the pentacoordinated intermediate E with
the hydroxy group at the opposite apical position.21 Then,
deprotonation and tandem breaking of another S-O bond
in C, E take place to give the highly diastereoselective
formation of the corresponding sulfoxides 7a and 8a with
SS and RS absolute configurations at sulfur, respectively.
However, recent research on the kinetic study of the
hydrolysis of the achiral spirosulfuranes indicates that
the dissociative mechanism might be an alternative
pathway to account for the stereochemical results of the
hydrolysis of spirosulfurane 5a .13b-d The stereochemical
outcome can be explained readily using the dissociative
mechanism by considering the diastereoselective forma-
tion of the sulfonium cation as the key intermediate in
hydrolysis of the spirosulfurane 5a (Scheme 7). Thus,
under the acidic condition, the initial protonation of 5a
takes place at the oxygen of S-O(alkoxy) which leads to
the easier cleavage of the S-O(alkoxy) bond to form the
intermediate sulfonium cation F ; then attack of H2O from
the â-side of the pseudoaxial direction onto the sulfonium
Con clu sion s
In conclusion, we have accomplished the synthesis of
a series of optically pure spirosulfuranes 5a -e, using the
2-exo-hydroxy-10-bornyl group as a chiral ligand, in high
yield and with excellent diastereoselectivity. The defined
structures were determined by X-ray analyses. The
stereochemistry of the hydrolysis of the spirosulfuranes
is dramatically affected by the reactivity of the apical
S-O bonds and the reaction conditions. Both of the
diastereomers of the optically pure sulfoxides could be
obtained by the hydrolysis of the spirosulfurane under
different conditions. These results are helpful for the
understanding of the stereochemistry of nuclophilic reac-
tions concerning multicoordinated heteroatom com-
pounds. The role of the apical ligands on the stereochem-
istry of nucleophilic reactions of the spirosulfuranes is
(20) The basicity of ethers (pKBH+ ) -3.5) is generally stronger than
that of esters (pKBH+ ) -6.5). March, J . Advanced Organic Chemis-
try: Reactions, Mechanisms, and Structure; Wiley-Interscience: New
York, 1992; p 250. Since the lack of the precise data of the basicity of
the two S-O groups in the alkoxy(acyloxy)spirosulfuranes, we think
data cited herein is reasonable to support the order of the protonation
of the two S-O groups proposed. Considering the central sulfur as a
carbon atom, the basicity of the two oxygens in the structure of C-O-
S-O-C(dO) should have similar order as that of C-O-C-O-C(d
O). However, the two oxygen atoms might influence each other through
the hypervalent O-S-O bond system, which might be different from
that of the O-C-O system. Further investigation of the reactions using
the computer calculation is ongoing, and the results will be reported
elsewhere.
(22) The S-O (acyloxy) bond is expected to hydrolyze easier
compared with the S-O (alkoxy) bond in alkoxy(acyloxy)spirosul-
furanes since the S-O (acyloxy) bond is longer and more negative
charge is distributed on the S-O (acyloxy) bond than S-O (alkoxy),
see: ref 13a.
(23) Yamakoshi, Y. N.; Ge, W. Y.; Okayama, K.; Takahashi, T.;
Koizumi, T. Heterocycles 1996, 42, 129-133.
(21) The pentacoordinated intermediates (C and E) can be reason-
ably considered as with the TBP geometry, and the most electro-
negative groups in C and E are expected to occupy axial positions.

Hydrolysis of Optically Pure Spirosulfuranes
J . Org. Chem., Vol. 63, No. 25, 1998 9381
temperature overnight. After acidification with 2 N HCl (ca.
5 mL), the reaction mixture was extracted with CH2Cl2 (75
mL × 3). The combined organic layer was then washed with
H2O (15 mL × 2) followed by brine (15 mL × 1) and dried over
MgSO4. Evaporation of the solvent under reduced pressure
afforded the product 4c (570 mg) in quantitative yield as a
white solid. (Z/E ) ca. 4/1). IR (neat) 2952, 1681 cm-1; 1H NMR
δ: (Z)-4c: 0.87 (s, 3H), 1.0-1.2 (m, 1H), 1.08 (s, 3H), 1.2-1.8
(m, 8H), 2.78 (d, J ) 12.1, 1H), 3.21 (d, J ) 12.1, 1H), 3.94
(dd, J ) 3.8, 8.2, 1H), 5.86 (d, J ) 9.9, 1H), 7.38 (d, J ) 9.9,
1H); (E)-4c: 0.90 (s, 3H), 1.0-1.2 (m, 1H), 1.10 (s, 3H), 1.2-
1.8 (m, 8H), 2.7 (d, J ) 12.1, 1H), 3.19 (d, J ) 12.1, 1H), 3.90
(dd, J ) 3.3, 8.0, 1H), 5.81 (d, J ) 14.9, 1H), 7.91 (d, J ) 15.4,
1H); MS m/z: 257 (M+ + 1), 256 (M+); HRMS calcd for
C13H20O3S: 256.1133. Found 256.1114.
expected to be utilized in the design of novel methods
for the synthesis of optically active chalcogenonium
compounds with a given stereochemistry on the central
chlcogen atom.
Exp er im en ta l Section
Gen er a l Meth od s. Common experimental procedures and
instrumentation have been described previously.7j Spectro-
scopic measurements were carried out with the following
instruments: 17O NMR, Varian Unity 500 (67.8 MHz) for
solutions in CDCl3 with H217O (0 ppm) as an external standard.
Coupling constants (J ) are given in hertz. H217O and H218O
were purchased from Matheson Co.
2-({(1S,2R,4R)-2-H yd r oxy-7,7-d im et h ylb icyclo[2.2.1]-
h ep ta n -1-yl}m eth ylth io)ben zoic a cid (4a ). To a stirred
suspension of NaH (60%, 336 mg, 8.4 mmol) in dry benzene
(16 mL) was added thiosalicyclic acid (616 mg, 4.0 mmol) at 0
°C under N2 atmosphere. After completion of addition (5 min),
DMF (8 mL) was added to the mixture at 0 °C, and the solution
was stirred until a clear solution was obtained (ca. 20 min).
Then (1S)-(-)-10-iodo-2-exo-bornanol (1.12 g, 4.0 mmol) in dry
benzene (2 mL) was added dropwise to the mixture at 0 °C,
and the whole mixture was stirred at 95 °C for 6 h. The
reaction was quenched with H2O (6 mL) followed by acidifica-
tion with 1 N HCl, and the mixture was extracted with AcOEt
(70 mL × 3). The combined extracts were washed with water
(15 mL × 3) followed by brine (10 mL × 1) and dried over
MgSO4. After removal of the solvent, the residual oil was
purified by column chromatography (hexane/AcOEt ) 1/1) to
give pure product 4a (718 mg, 59%) as colorless crystals: mp
193-195 °C; [R]26D -8.08° (c 0.967, EtOH); IR (KBr) 2952, 1682
cm-1; 1H NMR δ: 0.91 (s, 3H), 1.12 (s, 3H), 1.24-1.41 (m, 3H),
1.58-1.84 (m, 6H), 2.89 (d, J ) 9.9, 1H),3.21 (d, J ) 10.4, 1H),
4.08 (dd, J ) 3.9, 7.7, 1H), 7.24-7.29 (m, 1H), 7.50-7.52 (m
2H), 8.08 (d, J ) 7.1, 1H); 13C NMR δ: 20.3, 21.1, 27.5, 31.1,
33.4, 39.6, 45.3, 48.5, 52.0, 76.7, 124.9, 131.1, 132.3, 132.7,
133.2, 133.3, 164.7; MS m/z: 306 (M+), 288 (M+ - 18). Anal.
Calcd for C17H22O3S: C, 66.64; H, 7.24. Found: C, 66.67; H,
7.07.
Eth yl-(Z)-3-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo-
[2.2.1]h ep ta n -1-yl}m eth ylth io)cr oton a te. To a solution of
(-)-10-mercaptoisoborneol (168 mg, 1.0 mmol) and ethyl
2-butynoate (112 mg, 1.0 mmol) in EtOH-H2O (9:1) (5 mL)
was added Et3N (5 drops) at room temperature under N2
atmosphere. The mixture was then stirred at room tempera-
ture for 24 h. The solvent was evaporated, and the residue
was then extracted from H2O (10 mL) with EtOAc (50 mL ×
3). The combined organic layer was washed with H2O (10 mL
× 1) followed by brine (10 mL × 1) and dried over MgSO4.
Removal of the solvent under reduced pressure afforded the
crude products which were then purified by chromatography
(hexane/EtOAc ) 10/1 to 5/1) on silica gel gave product (180
mg, 44%) yield as a colorless oil; [R]26D ) -39.9° (c 0.94, CHCl3);
1
IR (neat) 2953, 1698 cm-1; H NMR δ: 0.87 (s, 3H), 1.08 (s,
3H), 1.02-1.10 (m, 1H), 1.30-1.41 (m, 1H), 1.27 (t, J ) 7.1,
3H), 1.50-1.62 (m, 2H), 1.68-1.79 (m, 4H), 2.28 (d, J ) 1.1,
3H), 2.80 (d, J ) 10.4, 1H), 3.21 (d, J ) 10.4, 1H), 3.97-4.09
(m, 1H), 4.16 (q, J ) 7.1, 2H), 5.83 (d, J ) 1.1, 1H); 13C NMR
δ: 14.5, 20.1, 20.8, 24.4, 27.2, 29.8, 30.5, 39.8, 45.1, 48.1, 51.4,
59.6, 75.9, 112.2, 158.4, 166.1; MS m/z: 299 (M+ + 1), 298 (M+);
HRMS calcd for C16H26O3S: 298.1602. Found 298.1580.
Z-3-({(1S,2R,4R)-2-Hyd r oxy-7,7-d im eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth ylth io)cr oton ic Acid (4d ). To a solution
of ethyl-(Z)-3-({(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]-
heptan-1-yl}methylthio)crotonate (233 mg, 0.78 mmol) in
THF-H2O-EtOH (1/1/1, 6 mL) was added a solution of 2 N
aqueous NaOH (4 mL, 8 mmol), and then the reaction mixture
was stirred under N2 atmosphere at room temperature for 27
h. After acidification with 1 N HCl (ca. 10 mL), the reaction
mixture was extracted with CH2Cl2 (50 mL × 3). The combined
organic layer was then washed with H2O (10 mL × 1) followed
by brine (10 mL × 1) and dried over MgSO4. Evaporation of
the solvent under reduced pressure afforded the crude product
which, after purification by chromatography (hexane/EtOAc
) 2/1), gave pure product 4d (97 mg, 46%) as a white solid:
mp 145-147 °C; [R]26D -43.54° (c 1.05, CHCl3); IR (KBr) 2953,
2-({(1S,2R,4R)-2-H yd r oxy-7,7-d im et h ylb icyclo[2.2.1]-
h ep ta n -1-yl}m eth ylth io)n icotin ic a cid (4b). To a stirred
suspension of NaH (60%, 84 mg, 2.1 mmol) in dry benzene (4
mL) was added 2-mercaptonicotinic acid (155 mg, 1 mmol) at
0 °C under N2 atmosphere. After completion of addition (5
min), DMF (2 mL) was added to the mixture at 0 °C, and the
solution was stirred until a clear solution was obtained (ca.
20 min). Then (1S)-(-)-10-iodo-2-exo-bornanol (280 mg, 1.0
mmol) in dry benzene (1 mL) was added dropwise to the
mixture at 0 °C, and the whole mixture was stirred at 120 °C
for 5.5 h. The reaction was quenched with H2O (4 mL) followed
by acidification with 1 N HCl to pH ) 6, and the mixture was
extracted with AcOEt (60 mL × 3). The combined extracts were
washed with water (10 mL × 3) followed by brine (10 mL) and
dried over MgSO4. After removal of the solvent, the residual
oil was purified by column chromatography (hexane/AcOEt )
1/1) to give pure product 4b (161 mg, 52%) as colorless
1
1672 cm-1; H NMR δ: 0.87 (s, 3H), 1.05-1.09 (m, 1H), 1.07
(s, 3H), 1.34-1.35 (m, 1H), 1.49-1.53 (m, 1H), 1.70-1.79 (m,
4H), 2.30 (s, 3H), 2.79 (d, J ) 10.4, 1H), 3.20 (d, J ) 10.4,
1H), 3.98 (dd, J ) 3.8, 8.2, 1H), 5.84, (s, 1H); 13C NMR δ: 20.3,
20.9, 24.9, 27.4, 30.2, 30.72, 39.9, 45.2, 48.4, 51.6, 76.2, 111.8,
161.7, 170.9; MS m/z: 272 (M+ + 2). Anal. Calcd for
crystals: mp 152-154 °C; [R]26 +73.33° (c 1.03, EtOH); IR
C
14H22O3S: C, 62.19; H, 8.20. Found: C, 62.44; H, 8.20.
D
(KBr) 2955, 1712 cm-1; 1H NMR δ: 0.92 (s, 3H), 1.0-1.05 (m,
1H), 1.20 (s, 3H), 1.29-1.40 (m, 1H), 1.60-1.82 (m, 5H), 2.85
(d, J ) 14.8, 1H), 3.78 (dd, J ) 3.3, 7.7, 1H), 3.85 (d, J ) 14.8,
1H), 7.13 (dd, J ) 4.9, 7.7, 1H), 8.33 (dd, J ) 2.2, 7.7, 1H),
8.56 (dd, J ) 2.2, 4.9, 1H); 13C NMR δ: 20.5, 21.1, 27.4, 29.8,
31.7, 38.9, 45.8, 48.2, 53.2, 75.9, 118.8, 123.2, 140.6, 152.0,
163.8, 168.7; MS m/z: 307 (M+), 289 (M+ - 18). Anal. Calcd
for C16H21NO3S: C, 62.51; H, 6.89; N, 4.56. Found: C, 62.26;
H, 6.89; N, 4.28.
3-({(1S,2R,4R)-2-H yd r oxy-7,7-d im et h ylb icyclo[2.2.1]-
h ep ta n -1-yl}m eth ylth io)a cr ylic Acid (4c). To a solution of
methyl-3-({(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]-
heptan-1-yl}methylthio)acrylate23 (600 mg, Z/ E ) ca. 4/1, 2.22
mmol) in THF-H2O-EtOH (1/1/1, 15 mL) was added a
solution of 1 N aqueous NaOH (8 mL, 8 mmol), and then the
reaction mixture was stirred under N2 atmosphere at room
E t h yl-3-({(1S,2R,4R)-2-H yd r oxy-7,7-d im et h ylb icyclo-
[2.2.1]h ep ta n -1-yl}m eth ylth io)p r op ion a te. To a stirred
suspension of NaH (60%, 84 mg, 2.1 mmol) in dry benzene (8
mL) was added ethyl 3-mercaptopropionate (268 mg, 2 mmol)
at 0 °C. After completion of addition (5 min), DMF (4 mL) was
added to the mixture at 0 °C, and the solution was stirred until
a clear solution was obtained (ca. 20 min). Then (1S)-(-)-10-
iodo-2-exo-bornanol (550 mg, 1.96 mmol) in dry benzene (1 mL)
was added dropwise to the mixture at 0 °C, and the whole
mixture was stirred at 0 °C to room temperature for 6.5 h
under N2 atmosphere. The reaction was quenched with H2O
(4 mL) and acidified with 1 N HCl. The mixture was then
extracted with AcOEt (60 mL × 3). The combined extracts were
washed with water (10 mL × 3) followed by brine (10 mL) and
dried over MgSO4. After removal of the solvent, the residual
oil was purified by column chromatography (hexane/AcOEt )

9382 J . Org. Chem., Vol. 63, No. 25, 1998
Zhang et al.
40/1 to 10/1) to give pure product (280 mg, 61%) as a colorless
1.22 (s, 3H), 1.82-2.0 (m, 4H), 2.32-2.48 (m, 1H), 3.45 (d, J
) 14.5, 1H), 4.56 (d, J ) 14.3, 1H), 5.07 (dd, J ) 3.3, 7.7, 1H),
7.68 (dd, J ) 4.4, 7.7, 1H), 8.52 (dd, J ) 1.6, 7.7, 1H), 8.82
(dd, J ) 1.6, 4.5, 1H); 13C NMR δ: 20.4, 20.5, 26.8, 28.0, 30.0,
37.9, 45.6, 46.9, 54.9, 58.3, 97.5, 111.5, 127.0, 139.2, 152.0,
200.4; MS m/z: 306 (M+ + 1). Anal. Calcd for C16H19NO3S: C,
62.93; H, 6.27; N, 4.59. Found: C, 62.61; H, 6.17; N, 4.17.
Recrystallization of the product from hexane-CH2Cl2 gave
crystals which were suitable for X-ray analysis. Crystal-
lographic data of 5b: C16H19NO3S, MW ) 305.39, orthorhom-
bic, space group P212121 (no. 19) with a ) 11.144(3) Å, b )
12.670(3) Å, c ) 10.615(3) Å, V ) 1498.8(6) Å3, Z ) 4, density-
(calcd) ) 1.353 g cm-3, F(000) ) 648, λ ) 0.71069 Å, T ) 293
K, µ (Mo-KR) ) 2.25 cm-1. Intensity data were collected on a
Rigaku AFC7R diffractometer using a 0.20 × 0.20 × 0.25 mm3
sized crystal; 1987 unique reflections; 1264 with I > 3.00σ(I)
were used in refinement; R ) 3.9%, Rw ) 3.9%.
oil. [R]26 -29.8° (c 1.17, CHCl3); IR (neat) 2953, 1736 cm-1
;
D
1H NMR δ: 0.82 (s, 3H), 1.05 (s, 3H), 1.26 (t, J ) 7.2, 3H),
1.01-1.30 (m, 2H), 1.46-1.53 (m, 1H), 1.65-1.80 (m, 4H),
2.56-2.66 (m, 3H), 2.72-2.90 (m, 3H), 3.85 (dd, J ) 3.8, 8.2,
1H), 4.11-4.19 (m, 3H); 13C NMR δ: 14.5, 20.2, 20.9, 27.2,
27.4, 28.6, 31.2, 32.1, 35.0, 39.3, 45.3, 47.9, 52.3, 61.0, 172.1;
MS m/z: 287 (M+ + 1), 286 (M+); HRMS calcd for C15H26O3S:
286.1602. Found 286.1599.
3-({(1S,2R,4R)-2-H yd r oxy-7,7-d im et h ylb icyclo[2.2.1]-
h ep ta n -1-yl}m eth ylth io)p r op ion ic Acid (4e). To a solution
of ethyl 3-({(1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]-
heptan-1-yl}methylthio)propionate (60 mg, 0.21 mmol) in
THF-H2O-EtOH (1:1:1, 1.5 mL) was added a solution of 1 N
aqueous NaOH (0.5 mL, 0.5 mmol), and then the reaction
mixture was stirred under N2 atmosphere at room temperature
overnight. After acidification with 1 N HCl (ca. 1 mL) the
reaction mixture was extracted with CH2Cl2 (25 mL × 3). The
combined organic layer was then washed with H2O (5 mL ×
1) followed by brine (5 mL × 1) and dried over MgSO4.
Evaporation of the solvent under reduced pressure afforded
the crude product which, after purification by chromatography
(hexane/EtOAc ) 1/1) gave pure product 4e (45 mg, 83%) as a
yellow oil. [R]26D -40.39° (c 0.813, CHCl3); IR (neat) 2952, 1712
cm-1; 1H NMR δ: 0.82 (s, 3H), 1.01-1.06 (m, 2H), 1.04 (s, 3H),
1.17-1.20 (m, 1H), 1.70-1.77 (m, 4H), 2.59 (d, J ) 11.0, 1H),
2.58-2.86 (m, 7H), 3.88 (dd, J ) 3.8, 8.2, 1H); 13C NMR δ:
20.2, 20.9, 27.3, 28.3, 31.2, 32.2, 34.6, 39.2, 45.2, 47.9, 52.3,
76.9, 177.1; MS m/z: 259 (M+ + 1), 258 (M+); HRMS calcd for
Sp ir o[4H -3a ,6-m et h a n o-3H -1,2-b en zoxa su lfole-2,2′λ4-
[5H-1,2]oxa su lfol]-5′-on e, 5,6,7,7a -tetr a h yd r o-8,8-d im eth -
yl-, [2R-(2r,3a r,6r,7a â)]- (5c): 98%; mp 80-82 °C (hexane-
CH2Cl2); [R]26 -138.81° (c 0.97, CHCl3); IR (neat) 2957, 1657
D
cm-1; 1H NMR δ: 0.94 (s, 3H), 0.8-1.38 (m, 2H), 1.07 (s, 3H),
1.65-2.0 (m, 4H), 3.19 (d, J ) 14.3, 1H), 4.33 (dd, J ) 3.3,
7.5, 1H), 4.40 (d, J ) 14.3, 1H), 6.80 (d, J ) 6.0, 1H), 6.84 (d,
J ) 6.0, 1H); 13C NMR δ: 20.1, 20.3, 26.8, 28.4, 37.5, 45.6,
46.5, 54.2, 58.9, 95.7, 136.8, 144.6, 168.4; MS m/z: 256 (M+
+
2), 255 (M+ + 1), 254 (M+); HRMS calcd for C13H18O3S:
254.0977. Found 254.0982.
Sp ir o[4H-3a ,6-m eth a n o-3H-1,2-ben zoxa su lfole-2,2′λ4-3′-
m eth yl-[5H-1,2]oxa su lfol]-5′-on e, 5,6,7,7a -tetr a h yd r o-8,8-
d im eth yl-, [2R-(2r,3a r,6r,7a â)]- (5d ): 91%; mp 91-93 °C
C
13H22O3S: 258.1290. Found: 258.1299.
Gen er a l P r oced u r e for P r ep a r a t ion of Sp ir osu l-
fu r a n es 5a -e. To a solution of sulfide 4a -e (1.10 mmol) in
CH2Cl2 (50 mL) was added t-BuOCl (0.14 mL, 1.16 mmol)
dropwise at 0 °C under N2 atmosphere. The mixture was
stirred at 0 °C for 30 min followed by addition of Et3N (0.17
mL, 1.21 mmol) dropwise, and then the reaction was stirred
for 1.5 h at 0 °C to room temperature. The reaction mixture
was worked up by removal of the solvent and excess reagents
directly followed by diluting with H2O (5 mL). The aqueous
layer was extracted with EtOAc (50 mL × 3). The combined
organic layer was then washed with H2O (10 mL × 3) followed
by brine (10 mL × 1) and dried over MgSO4. Evaporation of
the solvent under reduced pressure afforded the crude product
which was purified by recrystallization to give the product
5a -d as colorless crystals. Spirosulfurane 5e was obtained
by evaporation of the solvent directly, and the yield was
caculated by the integration of the 1H NMR of the crude
products.
(hexane-CH2Cl2); [R]26 -25.90° (c 0.96, CHCl3); IR (KBr)
D
1
2952, 1662 cm-1; H NMR δ: 0.94 (s, 3H), 1.0-1.4 (m, 3H),
1.12 (s, 3H), 1.65-2.20 (m, 4H), 2.26 (s, 3H), 3.33 (d, J ) 14.3,
1H), 4.21 (dd, J ) 2.7, 7.1, 1H), 4.43 (d, J ) 14.8, 1H), 6.55 (s,
1H); 13C NMR δ: 16.1, 20.2, 20.4, 26.9, 28.3, 38.0, 45.3, 46.6,
53.9, 58.7, 95.6, 132.4, 155.4, 169.1; MS m/z: 269 (M+ + 1),
268 (M+); HRMS calcd for C14H20O3S: 268.1133. Found:
268.1169.
Sp ir o[4H -3a ,6-m et h a n o-3H -1,2-b en zoxa su lfole-2,2′λ4-
3′,4′-d ih yd r o-[5H-1,2]oxa su lfol]-5′-on e, 5,6,7,7a -tetr a h y-
d r o-8,8-d im eth yl-, [2R-(2r,3a r,6r, 7a â)]- (5e): 80%; 1H
NMR δ: 0.93 (s, 3H), 1.0-1.1 (m, 1H), 1.04 (s, 3H), 1.65-2.0
(m, 4H), 2.0-2.2 (m, 2H), 2.8-3.0 (m, 2H), 3.4-3.5 (m, 2H),
3.60 (d, J ) 14.3, 1H), 4.42 (dd, J ) 4.4, 7.7, 1H), 4.15 (d, J )
14.8, 1H).
(S
S)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep t a n -1-yl}m et h a n esu lfin yl)ben zoic Acid (7a ). To a
solution of spirosulfurane 5a (15 mg, 0.05 mmol) in EtOH (2
mL) was added 1 N HCl (0.1 mL, 0.1 mmol) at room temper-
ature under N2 atmosphere. The reaction mixture was then
stirred at room temperature for 48 h. After diluting with H2O
(1 mL), the reaction mixture was extracted with CH2Cl2 (10
mL × 3). The combined organic layer was then washed with
H2O (3 mL × 1) followed by brine (3 mL × 1) and dried over
MgSO4. Evaporation of the solvent under reduced pressure
afforded the crude product which, after purification by recrys-
tallization from CH2Cl2-EtOH, gave pure product 7a (15.5 mg,
Sp ir o[4H -3a ,6-m et h a n o-3H -1,2-b en zoxa su lfole-2,2′λ4-
[5H -1,2]b en zoxa t h iole]-5′-on e, 5,6,7,7a -t et r a h yd r o-8,8-
d im eth yl-, [2R-(2r,3a r,6r,7a â)] (5a ): 96%; mp 212-213 °C
(hexanes-EtOAc); [R]26 +88.79° (c 0.7667, CHCl3); IR (neat)
D
1
2985, 1664 cm-1; H NMR δ: 0.96 (s, 3H), 1.0-1.3 (m, 2H),
1.23 (s, 3H), 1.78-2.0 (m, 4H), 2.22-2.4 (m, 1H), 3.35 (d, J )
14.3, 1H), 4.51 (d, J ) 14.3, 1H), 4.56 (dd, J ) 3.3, 7.7, 1H),
7.64-7.81 (m, 3H), 8.20-8.24 (m, 1H); 13C NMR δ: 20.3, 20.5,
26.9, 28.2, 37.8, 45.4, 46.8, 55.1, 59.4, 94.5, 125.7, 130.4, 132.1,
132.7, 134.5, 138.6, 168.3; MS m/z: 305 (M+ + 1), 304 (M+).
Anal. Calcd for C17H20O3S: C, 67.07; H, 6.62. Found: C, 66.96;
H, 6.46.
98%) as colorless crystals: mp 202-204 °C; [R]26 -268.37° (c
D
1.26, EtOH); IR (KBr) 2943, 1677 cm-1; H NMR δ: 0.84 (s,
1
Recrystallization of the product from hexanes-EtOAc gave
crystals which were suitable for X-ray analysis. Crystal-
lographic data of 5a : C17H20O3S, MW ) 304.40, orthorhombic,
space group P212121 (no. 19) with a ) 11.206(3) Å, b ) 12.282-
(2) Å, c ) 10.965(3) Å, V ) 1509.1(5) Å3, Z ) 4, density(calcd)
) 1.34 g cm-3, F(000) ) 648, λ ) 0.71069 Å, T ) 293 K, µ
(Mo-KR) ) 2.22 cm-1. Intensity data were collected on a
Rigaku AFC7R diffractometer using a 0.15 × 0.15 × 0.20 mm3
sized crystal; 1999 unique reflections; 766 with I > 3.00σ(I)
were used in refinement; R ) 4.2%, Rw ) 4.4%.
3H), 1.02 (s, 3H),1.20-1.30 (m, 1H), 1.50-1.62 (m, 1H), 1.71-
2.07 (m, 7H), 2.50 (d, J ) 13.2, 1H), 3.37 (d, J ) 13.2, 1H),
4.50 (t, J ) 5.5, 1H), 7.60 (t, J ) 7.2, 1H), 7.87 (t, J ) 7.2),
8.19 (d, J ) 7.7, 1H), 8.36 (d, J ) 7.7, 1H); 13C NMR δ: 20.4,
20.9, 27.8, 30.7, 30.8, 44.7, 49.1, 52.1, 60.4, 124.9, 126.6, 130.3,
131.7, 134.4, 150.2, 168.5; MS m/z: 304 (M+ - 18). Anal. Calcd
for C17H22O4S: C, 63.33; H, 6.88. Found: C,63.09; H, 6.83.
Recrystallization of the product from CH2Cl2-EtOH gave
crystals which were suitable for X-ray analysis. Crystal-
lographic data of 7a : C17H22O4S, MW ) 322.42, monoclinic,
space group P21 (no. 4) with a ) 6.961(4) Å, b ) 10.993(3) Å,
c ) 10.765(4) Å, â ) 103.04(4)°, V ) 802.6(6) Å3, Z ) 2, density-
(calcd) ) 1.334 g cm-3, F(000) ) 344.00, λ ) 0.71069 Å, T )
293 K, µ (Mo-KR) ) 2.17 cm-1. Intensity data were collected
on a Rigaku AFC7R diffractometer using a 0.30 × 0.20 × 0.20
Sp ir o[4H -3a ,6-m et h a n o-3H -1,2-b en zoxa su lfole-2,2′λ4-
[5H-1,2]-3′′-p icoloxa th iole]-5′-on e, 5,6,7,7a -tetr a h yd r o-8,8-
d im eth yl-, [2R-(2r,3a r,6r,7a â)] (5b): 94%; mp 204-205 °C
(hexane-CH2Cl2); [R]26 +97.17° (c 1.227, CHCl3); IR (neat)
D
2955, 1665 cm-1; 1H NMR δ: 0.98 (s, 3H), 1.10-1.26 (m, 2H),

Hydrolysis of Optically Pure Spirosulfuranes
J . Org. Chem., Vol. 63, No. 25, 1998 9383
mm3 sized crystal; 2084 unique reflections; 1138 with I >
3.00σ(I) were used in refinement; R ) 4.1%, Rw ) 4.2%.
(SS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)a cr ylic Acid (7c). Recrys-
tallization of 5c (131 mg, 0.51 mmol) from EtOH gave sulfoxide
(CD3OD) δ: 0.85 (s, 3H), 1.02 (s, 3H),1.2-1.29 (m, 2H), 1.61-
1.69 (m, 1H), 1.76-1.89 (m, 4H), 2.0-2.13 (m, 1H), 3.13 (d, J
) 12.6, 1H), 3.21 (d, J ) 13.2, 1H), 3.23-3.31 (m, 1H), 4.13-
4.17 (m, 1H), 7.7-7.74 (m, 1H), 8.5 (d, J ) 7.7, 1H), 8.95-
8.96 (m, 1H); 13C NMR (CD3OD) δ: 20.2, 20.9, 28.0, 31.3, 39.6,
46.5, 49.4, 53.0, 56.9, 78.3, 126.7, 128.3, 128.6, 128.9, 141.0,
164.8; MS m/z: 296. Anal. Calcd for C16H21NO4S: C, 59.42;
H, 6.54; N, 4.44. Found: C, 59.45; H, 6.55; N, 4.22.
7c (122 mg, 94%) as colorless crystals: mp 140-141 °C; [R]26
D
-18.13° (c 0.82, CHCl3) or -71.81° (c 1.08, EtOH); IR (KBr)
1
2927, 1673 cm-1; H NMR δ: 0.87 (s, 3H), 1.02 (s, 3H),1.08-
1.43 (m, 3H), 1.72-2.0 (m, 6H), 2.97 (d, J ) 13.2, 1H), 3.2 (d,
J ) 13.2, 1H), 4.33 (dd, J ) 3.8, 7.7, 1H), 6.31 (d, J ) 9.9, 1H),
7.14 (d, J ) 9.9, 1H); 13C NMR δ: 14.6, 20.2, 20.9, 27.2, 31.0,
39.5, 45.2, 48.2, 51.2, 59.7, 108.9, 159.1, 165.2; MS m/z: 254
(M+ - 18). Anal. Calcd for C13H20O4S: C, 57.31; H, 7.41.
Found: C, 57.64; H, 7.52.
Recrystallization of the product from EtOAc-CH2Cl2 gave
crystals which were suitable for X-ray analysis. Crystal-
lographic data of 7c: C13H20O4S, MW ) 272.36, orthorhombic,
space group P212121 (no. 19) with a ) 11.063(3) Å, b ) 12.150-
(3) Å, c ) 10.059(2) Å, V ) 1352.1(5) Å3, Z ) 4, density(calcd)
) 1.338 g cm-3, F(000) ) 584.00, λ ) 0.71069 Å, T ) 293 K, µ
(Mo-KR) ) 2.43 cm-1. Intensity data were collected on a
Rigaku AFC7R diffractometer using a 0.20 × 0.20 × 0.20 mm3
sized crystal; 1804 unique reflections; 962 with I > 3.00σ(I)
were used in refinement; R ) 4.3%, Rw ) 4.2%.
Recrystallization of the product from hexane-CH2Cl2 gave
crystals which were suitable for X-ray analysis. Crystal-
lographic data of 8b: C16H21NO4S, MW ) 323.41, monoclinic,
space group P21 (no. 4) with a ) 7.235(2) Å, b ) 12.913(4) Å,
c ) 8.858(2) Å, â ) 91.56(2)°, V ) 828.4(3) Å3, Z ) 2, density
(calcd) ) 1.296 g cm-3, F(000) ) 344.00, λ ) 0.71069 Å, T )
293 K, µ (Mo-KR) ) 2.12 cm-1. Intensity data were collected
on a Rigaku AFC7R diffractometer using a 0.25 × 0.25 × 0.20
mm3 sized crystal; 1995 unique reflections; 1709 with I >
3.00σ(I) were used in refinement; R ) 3.7%, Rw ) 3.8%.
(RS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)a cr ylic Acid (8c). The pro-
cedure described in the preparation of 8a was similarly applied
for 5c (32 mg, 0.125 mmol) to prepare 8c (33 mg, 97%) as
colorless crystals: mp 158-160 °C; [R]26 +214.17° (c 1.20,
D
EtOH); IR (KBr) 2954, 1684, 1613 cm-1; 1H NMR (CD3OD) δ:
0.88 (s, 3H), 1.09 (s, 3H),1.15-1.33 (m, 2H), 1.49-1.56 (m, 1H),
1.72-1.91 (m, 5H), 2.93 (d, J ) 13.2, 1H), 3.30-3.31 (m, 1H),
3.49 (d, J ) 13.2, 1H), 4.0 (dd, J ) 3.8, 7.7, 1H), 6.43 (d, J )
9.9, 1H), 7.01 (d, J ) 9.9, 1H); 13C NMR (CD3OD) δ: 20.3, 20.9,
27.9, 31.3, 39.6, 46.5, 49.4, 52.7, 55.8, 78.2, 127.5, 156.1, 166.8;
MS m/z: 273 (M+ + 1). Anal. Calcd for C13H20O4S: C, 57.33;
H, 7.40. Found: C, 56.73; H, 7.29.
(SS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)cr oton ic Acid (7d ). Recrys-
tallization of 5d (44 mg, 0.16 mmol) from EtOH gave sulfoxide
7d (41 mg, 91%) as colorless crystals: mp 155-157 °C; [R]26
D
-154.41° (c 1.05, EtOH); IR (KBr) 2955, 1687 cm-1; H NMR
1
δ: 0.85 (s, 3H), 1.01 (s, 3H),1.06-1.58 (m, 3H), 1.7-2.0 (m,
6H), 2.28 (d, J ) 1.65, 3H), 2.81 (d, J ) 12.6, 1H), 3.06 (d, J )
12.6, 1H), 4.34 (dd, J ) 3.3, 7.0, 1H), 6.21 (d, J ) 1.65, 1H);
13C NMR δ: 15.8, 20.2, 20.8, 27.7, 30.6, 38.9, 44.6, 49.1, 51.6,
56.6, 76.7, 120.3, 167.1, 168.4; MS m/z: 287 (M+ + 1), 285 (M+
- 1), 268 (M+ - 18). Anal. Calcd for C14H22O4S: C, 58.72; H,
7.75. Found: C, 58.78; H, 7.75.
(RS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)cr oton ic Acid (8d ). The pro-
cedure described in the preparation of 8a was similarly applied
for 5d (62 mg, 0.23 mmol) to prepare 8d (64 mg, 97%) as
colorless crystals: mp 188-190 °C; [R]26 +228.86° (c 1.50,
D
1
(RS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep t a n -1-yl}m et h a n esu lfin yl)b en zoic Acid (8a ). To a
solution of spirosulfurane 5a (34.5 mg, 0.11 mmol) in EtOH
(2 mL) was added 1 N NaOH (0.2 mL, 0.2 mmol) at 0 °C under
N2 atmosphere. The reaction mixture was then stirred at 0
°C for 0.5 h. After acidification with 1 N HCl (ca. 0.5 mL), the
reaction mixture was extracted with CH2Cl2 (15 mL × 3). The
combined organic layer was then washed with H2O (6 mL ×
1) followed by brine (6 mL × 1) and dried over MgSO4.
Evaporation of the solvent under reduced pressure afforded
the crude product which, after purification by recrystallization
from EtOAc-CH2Cl2 gave pure product 8a (31 mg, 88%) as
EtOH); IR (KBr) 2959, 1687, 1630 cm-1; H NMR δ: 0.82 (s,
3H), 1.08 (s, 3H),1.09-1.17 (m, 1H), 1.62-1.71 (m, 1H), 1.74-
1.83 (m, 7H), 2.27 (s, 3H), 2.72 (d, J ) 12.1, 1H), 3.37 (d, J )
12.6, 1H), 4.12 (dd, J ) 3.8, 8.2, 1H), 6.24 (s, 1H); 13C NMR δ:
15.8, 20.2, 20.9, 27.4, 30.4, 38.7, 45.5, 48.7, 52.0, 55.0, 78.2,
120.5, 167.0, 167.2; MS m/z: 287 (M+ + 1), 268 (M+ - 18).
Anal. Calcd for C14H22O4S: C, 58.72; H, 7.75. Found: C, 58.78;
H, 7.75.
Gen er a l P r oced u r e of Isom er iza tion of Su lfoxid e 7a
a n d 8a . To a solution of sulfoxide 7a (or 8a ) (0.05 mmol) in
EtOH (2 mL) was added 1 N HCl (or NaOH) at room
atmosphere under nitrogen atmosphere. The reaction mixture
was then stirred under the conditions shown in Table 2.
Similar workup as in the case of hydrolysis of 5a afforded the
products in yields exhibited in Table 2. The diastereomeric
ratio of the sulfoxides was determined by the 1H NMR
integration of the crude products.
colorless crystals: mp 208-210 °C; [R]26 +190.19° (c 0.76,
D
EtOH); IR (KBr) 2957, 1699 cm-1; H NMR (CD3OD) δ: 0.82
1
(s, 3H), 1.01 (s, 3H),1.22-1.27 (m, 1H), 1.60-1.70 (m, 1H),
1.75-1.87 (m, 5H), 2.01-2.15 (m, 1H), 3.00 (d, J ) 13.2, 1H),
3.17 (d, J ) 12.6, 1H), 3.30-3.32 (m, 1H), 4.14-4.92 (m, 1H),
7.68 (dt, J ) 1.1, 7.7, 1H), 7.91 (dt, J ) 1.1, 7.7, 1H), 8.17 (dd,
J ) 1.6, 7.7, 1H), 8.24 (dd, J ) 1.6, 7.7, 1H); 13C NMR (CD3-
OD) δ: 20.2, 20.9, 27.9, 31.4, 39.4, 46.6, 53.0, 60.1, 78.4, 124.9,
(SS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)ben zoic Acid -18O (7a -18O).
To a solution of spirosulfurane 5a (31 mg, 0.10 mmol) in
anhydrous EtOH (2 mL) and H218O (0.005 mL, 97 atom % 18O)
was added 1 N HCl (in Et2O, 0.01 mL, 0.01 mmol) at room
temperature under N2 atmosphere. The reaction mixture was
then stirred at room temperature for 48 h. Evaporation of the
128.9, 131.7, 132.3, 134.8, 148.2, 167.9; MS m/z: 304 (M+
18). Anal. Calcd for C17H22O4S: C, 63.33; H, 6.88. Found: C,
63.75; H, 6.91.
-
Recrystallization of the product from hexanes-EtOAc-CH2-
Cl2 gave crystals which were suitable for X-ray analysis.
Crystallographic data of 8a : C17H22O4S, MW ) 322.42, ortho-
rhombic, space group P212121 (no. 19) with a ) 13.124(3) Å, b
) 14.720(3) Å, c ) 8.659(2) Å, V ) 1672.8(5) Å3, Z ) 4, density-
(calcd) ) 1.280 g cm-3, F(000) ) 688.00, λ ) 0.71069 Å, T )
293 K, µ (Mo-KR) ) 2.08 cm-1. Intensity data were collected
on a Rigaku AFC7R diffractometer using a 0.20 × 0.20 × 0.25
mm3 sized crystal; 2216 unique reflections; 1464 with I >
3.00σ(I) were used in refinement; R ) 4.2%, Rw ) 4.1%.
(RS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)n icotin ic Acid (8b). The
procedure described in the preparation of 8a was similarly
applied for 5b (104 mg, 0.34 mmol) to prepare 8b (93 mg, 90%)
solvent under reduced pressure afforded the product 7a -18
O
(32 mg, 97%) as a white solid.
(RS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)ben zoic Acid -18O (8a -18O).
To a solution of spirosulfurane 5a (31 mg, 0.10 mmol) in
anhydrous EtOH (2 mL) was added NaOH (0.015 mL, 0.15
mmol, prepared from 7.8 mg NaOH and 0.02 mL H218O, 97
atom % 18O) at 0 °C under N2 atmosphere. The reaction
mixture was then stirred at 0 °C for 0.5 h. After acidification
with 1 N HCl (in Et2O, 0.2 mL, 0.2 mmol), the reaction mixture
was diluted with anhydrous CH2Cl2 (15 mL) and dried over
MgSO4. Evaporation of the solvent under reduced pressure
afforded the product 8a -18O (33 mg, 99%) as a white solid.
(SS)-Me t h yl-2-({(1S,2R,4R)-2-H yd r oxy-7,7-d im e t h yl-
bicyclo[2.2.1]h epta n -1-yl}m eth a n esu lfin yl)ben zon a te (9).
as colorless crystals: mp 239-240 °C (CH2Cl2-hexane); [R]26
D
+130.02° (c 0.50, EtOH); IR (KBr) 2949, 1699 cm-1; H NMR
1

9384 J . Org. Chem., Vol. 63, No. 25, 1998
Zhang et al.
To a solution of sulfoxide 7a (30 mg, 0.093 mmol) in Et2O (8
mL) was added CH2N2 (ca. 2 mL in Et2O) at 0 °C under N2
atmosphere. The reaction mixture was then stirred at 0 °C to
room temperature for 3 h. Evaporation of solvent and excess
reagents afforded the pure product (30 mg, 96%) as a white
solid: mp 100-102 °C; [R]26D -284.74° (c 1.18, CHCl3); IR (KBr)
°C under N2 atmosphere. The reaction mixture was then
stirred at 0 °C to room temperature for 3 h. Evaporation of
solvent and excess reagents afforded the pure product (31 mg,
91%) as a white solid. MS m/z: 339 (M+ + 1), 320, 186, 154,
91.
(SS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)ben zoic Acid -17O (7a -17O).
To a solution of spirosulfurane 5a (31 mg, 0.10 mmol) in
anhydrous EtOH (2 mL) and H217O (0.012 mL, 20.3 atom %
17O) was added 1 N HCl (in Et2O, 0.01 mL, 0.01 mmol) at room
temperature under N2 atmosphere. The reaction mixture was
then stirred at room temperature for 48 h. Evaporation of the
1
2953, 1710 cm-1; H NMR δ: 0.81 (s, 3H), 1.04 (s, 3H),1.0-
1.2 (m, 1H), 1.30-1.42 (m, 1H), 1.6-2.2 (m, 5H), 2.59 (d, J )
13.7, 1H), 3.39 (d, J ) 13.2, 1H), 4.00 (s, 3H), 4.1-4.35 (m,
2H), 7.60 (t, J ) 7.7, 1H), 7.86 (t, J ) 7.7, 1H), 8.11 (t, J )
7.7, 1H), 8.70 (t, J ) 7.7, 1H); 13C NMR δ: 20.3, 20.8, 27.8,
30.8, 39.6, 44.7, 49.0, 52.3, 53.3, 59.7, 125.1, 126.1, 130.3, 130.9,
134.3, 150.0, 166.3; MS m/z: 337 (M+ + 1), 318 (M+ - 18),
184, 152, 91. Anal. Calcd for C18H24O4S: C, 64.26; H, 7.19.
Found: C, 64.22; H, 6.97.
solvent under reduced pressure afforded the product 7a -17
O
(31 mg, in 96%) as a white solid. 17O NMR δ: -8.103.
(RS)-2-({(1S,2R,4R)-2-Hydr oxy-7,7-dim eth ylbicyclo[2.2.1]-
h ep ta n -1-yl}m eth a n esu lfin yl)ben zoic Acid -17O (8a -17O).
To a solution of spirosulfurane 5a (30.5 mg, 0.10 mmol) in
anhydrous EtOH (2 mL) was added NaOH (0.015 mL, 0.17
mmol, prepared from 6.8 mg of NaOH and 0.015 mL of H217O,
20.3 atom % 17O) at 0 °C under N2 atmosphere. The reaction
mixture was then stirred at 0 °C for 0.5 h. After acidification
with 1 N HCl (in Et2O, 0.2 mL, 0.2 mmol), the reaction mixture
was diluted with anhydrous CH2Cl2 (15 mL) and dried over
MgSO4. Evaporation of the solvent under reduced pressure
afforded the product 8a -17O (31 mg, in 96%) as a white solid.
17O NMR δ: -9.184.
(RS)-Meth yl 2-({(1S,2R,4R)-2-Hyd r oxy-7,7-d im eth ylbi-
cyclo[2.2.1]h ep ta n -1-yl}m eth a n esu lfin yl)ben zon a te (10).
To a solution of sulfoxide 8a (60 mg, 0.19 mmol) in CH2Cl2
(25 mL) was added CH2N2 (ca. 2 mL in Et2O) at 0 °C under
N2 atmosphere. The reaction mixture was then stirred at 0
°C to room temperature for 3 h. Evaporation of solvent and
excess reagents afforded the pure product (63 mg, 100%) as a
white solid: mp 103-105 °C; [R]26 +196.11° (c 0.8, CHCl3);
D
IR (KBr) 2955, 1708 cm-1; H NMR δ: 0.80 (s, 3H), 1.03 (s,
1
3H),1.2-1.3 (m, 1H), 1.75-2.01 (m, 6H), 2.99 (d, J ) 12.6, 1H),
3.06 (d, J ) 12.6, 1H), 3.95 (s, 3H), 4.26 (dd, J ) 4.4, 7.7, 1H),
4.3-4.4 (br, 1H), 7.59 (dt, J ) 1.1, 7.7, 1H), 7.85 (dt, J ) 1.1,
7.7, 1H), 8.11 (dd, J ) 1.6, 7.7, 1H), 8.32 (dd, J ) 1.6, 7.7,
1H); 13C NMR δ: 20.2, 20.8, 27.4, 30.7, 38.7, 45.5, 48.5, 52.3,
52.9, 59.4, 124.7, 126.7, 130.4, 130.9, 134.1, 148.7, 165.6; MS
m/z: 337 (M+ + 1), 318 (M+ - 18), 184, 152, 91. Anal. Calcd
for C18H24O4S: C, 64.26; H, 7.19. Found: C, 64.33; H, 7.00.
(SS)-Meth yl 2-({(1S,2R,4R)-2-Hyd r oxy-7,7-d im eth ylbi-
Ack n ow led gm en t. This work was supported by
Grants-in-Aid for Scientific Research from the Ministry
of Education, Sciences, Sports and Culture, J apan No.
09470483 (T. K.), No. 092338213 (T. K.), No. 09239219
(T. K.), by Hoan Sha Foundation (T. K.), and by Uehara
Memorial Foundation (T. K.).
cyclo[2.2.1]h ep ta n -1-yl}m eth a n esu lfin yl)ben zon a te-18
O
(9-18O). To a solution of sulfoxide 7a -18O (32 mg, 0.1 mmol) in
Et2O (10 mL) was added CH2N2 (ca. 2 mL in Et2O) at 0 °C
under N2 atmosphere. The reaction mixture was then stirred
at 0 °C to room temperature for 3 h. Evaporation of solvent
and excess reagents afforded the pure product (33 mg, 98%)
as a white solid. MS m/z: 339 (M+ + 1), 320, 186, 154, 91.
(RS)-Meth yl 2-({(1S,2R,4R)-2-Hyd r oxy-7,7-d im eth ylbi-
Su p p or tin g In for m a tion Ava ila ble: Detailed structure
determination summary and listings of final atomic coordi-
nates, thermal parameters, bond lengths, and bond angles for
compounds 5b, 7c, and 8b (49 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
cyclo[2.2.1]h ep ta n -1-yl}m eth a n esu lfin yl)ben zon a te-18
O
(10-18O). To a solution of sulfoxide 8a -18O (33 mg, 0.10 mmol)
in CH2Cl2 (25 mL) was added CH2N2 (ca. 2 mL in Et2O) at 0
J O981330T