Sulfoxide-mediated asymmetric synthesis of glycosidase inhibitor precursors

Article abstract of DOI:10.1021/jo961774u

The highly diastereoselective DIBALH and DIBALH/ZnBr₂ reduction of enantiomerically pure (5S,(S)S)-3-ethoxy-5-(p-tolylsulfinyl)cyclopentenone (9)is used as a key step to the synthesis of oxazolidinone 2, a precursor of glycosidase inhibitor mannostatin. Compound 9 was obtained from 3-ethoxycyclopentenone by direct sulfinylation with (S)-N-benzyl-N-(p-tolylsulfinyl)propionamide.

Full text of DOI:10.1021/jo961774u

J . Org. Chem. 1997, 62, 2139-2143
2139
Su lfoxid e-Med ia ted Asym m etr ic Syn th esis of Glycosid a se In h ibitor
P r ecu r sor s
Ana B. Bueno, M. Carmen Carren˜o,* J ose´ L. Garc´ıa Ruano,* Ramo´n Go´mez Arraya´s, and
Mar´ıa M. Zarzuelo
Departamento de Quı´mica Orga´nica (C-I), Universidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
Received September 17, 1996X
The highly diastereoselective DIBALH and DIBALH/ZnBr2 reduction of enantiomerically pure (5S,-
(S)S)-3-ethoxy-5-(p-tolylsulfinyl)cyclopentenone (9) is used as a key step to the synthesis of
oxazolidinone 2, a precursor of glycosidase inhibitor mannostatin. Compound 9 was obtained from
3-ethoxycyclopentenone by direct sulfinylation with (S)-N-benzyl-N-(p-tolylsulfinyl)propionamide.
Sch em e 1
In tr od u ction
Glycosidase inhibitors possess a wide range of biologi-
cal properties1 including antitumoral and antiviral activi-
ties. Some of these compounds share the common
structural features of an aminopolyhydroxycyclopentane2
or cyclohexane3 moiety with defined stereochemistry. The
potential of these enzyme inhibitors as therapeutic agents
as well as their challenging structures have stimulated
intensive efforts in recent years directed toward their
stereocontrolled total synthesis.4 Several research groups
have focused attention on five-membered-ring derivatives
of the trehazolin5 and mannostatin6 family. One of the
routes to racemic mannostatin was reported by Trost6d,f
in 1994 (Scheme 1), but this strategy failed to provide
enantiomerically pure materials.6f
giving rise, after elimination of the sulfinyl group, to
enantiomerically pure carbinols. We successfully applied
this strategy to the synthesis of several natural mac-
rolides9 and various cyclohexanols.10 We decided to
extend this methodology to the synthesis of highly
functionalized cyclopentanols as an approach to glyco-
sidase inhibitors. In this paper, we report the asym-
metric synthesis of the oxazolidinone 2, a precursor of 1
(Scheme 1) in high optical purity, utilizing â-keto sul-
foxide reduction as a key step to achieve the proper
absolute stereochemistry.
In connection with our research devoted to the use of
sulfoxides in asymmetric synthesis,7 we found that
reduction of both cyclic8 and acyclic8b â-keto sulfoxides
could be effected in a highly stereocontrolled manner
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) (a) Review: Yoshikuni, Y. Trends Glycosci. Glycotechnol. 1991,
3, 184-192. (b) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2,
199-23. (c) Fellows, L. E.; New Sci. 1989, 123, 45. (d) Fellows, L. E.
Chem. Br. 1987, 23, 842.
(2) (a) Aoyagi, T.; Yamamoto, T.; Kojiri, K.; Morishima, H.; Nagai,
M.; Hamada, M.; Takeuchi, T.; Umezawa, H. J . Antibiot. 1989, 42,
883. (b) Morishima, H.; Kojiri, K.; Yamamoto, T.; Aoyagi, T.; Naka-
mura, H.; Iitaka, Y. J . Antibiot. 1989, 42, 1008 (mannostatin a). (c)
Ando, O.; Sataki, S.; Itoi, K.; Sato, A.; Nakajima, M.; Takahashi, S.;
Haruyama, H. J . Antibiot. 1991, 44, 1165 (trehazolin).
Resu lts a n d Discu ssion
(3) (a) Reviews: Suami, T.; Ogawa, S. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 21-90. Suami, T. Top. Curr. Chem. 1990, 154, 257-
283. (b) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.; Naka-
mura, H.; Iitaka, Y.; Takeuchi, T. J . Antibiot. 1990, 43, 49. (c) Horii,
S.; Fukase, H.; Kameda, Y.; Asano, N.; Matsui, K. J . Med. Chem. 1986,
29, 1038 (AO-128).
(4) For recent references of six-membered ring derivatives see: (a)
J ung, M. E.; Choe, S. W. T. J . Org. Chem. 1995, 60, 3280. (b) Hudlicky,
T.; Rouden, J .; Luna, H.; Allen, S. J . Am. Chem. Soc. 1994, 116, 5099.
(5) (a) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J . Org. Chem. 1994,
59, 813. (b) Shiozaki, M.; Arai, M.; Kobayashi, Y.; Kasuya, A.;
Miyamoto, S.; Furukawa, Y.; Takayama, T.; Haruyama, H. J . Org.
Chem. 1994, 59, 4450. (c) Kobayashi, Y.; Shiozaki, M.; Ando, O. J . Org.
Chem. 1995, 60, 2570. (d) Knapp, S.; Purandare, A.; Rupitz, K.;
Withers, S. G. J . Am. Chem. Soc. 1994, 116, 7461. (e) Goering, B. K.,
Li, J .; Ganem, B. Tetrahedron Lett. 1995, 36, 8905.
(6) (a) King, S. B.; Ganem, B. J . Am. Chem. Soc. 1994, 116, 562. (b)
Knapp, S.; Dhar, T. G. M. J . Org. Chem. 1991, 56, 4096. (c) Ganem,
B.; King, S. B. J . Am. Chem. Soc. 1991, 113, 5089. (d) Trost, B. M.;
Van Vranken, D. L. J . Am. Chem. Soc. 1991, 113, 6317. (e) Ogawa, S.;
Yuming, Y. J . Chem. Soc., Chem. Commun. 1991, 890. (f) Trost, B.
M.; Van Vranken, D. L. J . Am. Chem. Soc. 1993, 115, 444. (g) Li C.;
Fuchs, P. L. Tetrahedron Lett. 1994, 35, 5121. (h) Nishimura, Y.;
Umezawa, Y.; Adachi, H.; Kondo, S.; Takeuchi, T. J . Org. Chem. 1996,
61, 480. (i) Ogawa, S.; Kimura, H.; Vehida, C.; Ohashi, T. J . Chem.
Soc., Perkin Trans 1 1995, 1695. (j) Ingall, A. H.; Moore, P. R.; Roberts,
S. M. Tetrahedron: Asymmetry 1994, 5, 2155.
Our retrosynthetic analysis for 1 (Scheme 2) indicated
that compound 3 could be considered a potential precur-
sor because it could generate both the oxazolidinone ring
(by stereoselective intramolecular nucleophilic addition
at the vinyl sulfoxide moiety) and the enonic system
(ketal hydrolysis and desulfinylation). The synthesis of
3 could be achieved from 4 through conventional trans-
(7) For an overview of our work see: (a) Carren˜o, M. C. Chem. Rev.
1995, 95, 1717. (b) Solladie´, G.; Carren˜o, M. C. In Organosulphur
Chemistry: Synthetic Aspects; Page, B. C. P., Ed.; Academic Press:
London, 1995; p 1.
(8) (a) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Rubio, A. Tetrahedron
Lett. 1987, 28, 4861. (b) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Mart´ın,
A. M.; Pedregal, C.; Rodr´ıguez, J . H.; Rubio, A.; Sa´nchez, J .; Solladie´,
G. J . Org. Chem. 1990, 55, 2120. (c) Bueno, A. B.; Carren˜o, M. C.;
Garc´ıa Ruano, J . L.; Pen˜a, B.; Rubio, A.; Hoyos, M. A. Tetrahedron
Lett. 1994, 50, 9355.
(9) (a) Solladie´, G.; Rubio, A.; Carren˜o, M. C., Garc´ıa Ruano, J . L.
Tetrahedron: Asymmetry 1990, 1, 187. (b) Solladie´, G.; Maestro, M.
C.; Rubio, A.; Pedregal, C.; Carren˜o, M. C.; Garc´ıa Ruano, J . L. J . Org.
Chem. 1991, 56, 2317.
(10) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Garrido, M.; Ruiz, M. P.;
Solladie´, G. Tetrahedron Lett. 1990, 31, 6653.
S0022-3263(96)01774-4 CCC: $14.00 © 1997 American Chemical Society

2140 J . Org. Chem., Vol. 62, No. 7, 1997
Bueno et al.
Sch em e 2
Sch em e 4
Sch em e 3
afforded a higher yield (75%) of 9a + 9b in the same 80:
20 ratio, but in this case the ee of the major isomer 9a
was 96%. Repeated crystallizations of the 80:20 epimeric
mixture of 9a and 9b from ether containing 1 drop of 1
N NaOH solution afforded diastereomerically pure 9a .
As expected from previous â-keto sulfoxide reduc-
tions,8b,18 the treatment of 9a with DIBALH or DIBALH/
ZnBr2 afforded carbinols with the opposite configurations
at the hydroxyl center (Scheme 4). In the absence of
ZnBr2, an excess of DIBALH (3.5 equiv) was neccesary
to achieve a complete reaction. However, a 85:15 mixture
of trans-hydroxy sulfoxide 4t and the overreduced trans-
hydroxy thioether 10t was formed in these conditions.
The reaction with DIBALH and ZnBr2 cleanerly formed
cis-hydroxy sulfoxide 4c as the sole isolated product. The
configurations shown in Scheme 4 were assigned accord-
ing to the established mechanism of these reductions.8b,c
All attempts to isolate and purify compounds 4c or 4t
were unsuccessful due to their instability.19 Thus, the
synthesis was continued using 4c directly from the
reduction without further purification. As depicted in
Scheme 5, iodo acetal 11 was obtained by treatment of
4c with NIS in EtOH.20 The stereochemistry of 11 was
assigned on the basis of similar known reactions of
alkoxy-2-cyclopentene derivatives.21 Thus, the interme-
diate iodonium ion (I) should be formed from the steri-
cally less encumbered face of the starting hydroxy
sulfoxide, and the regioselective nucleophilic attack of
ethanol afforded 11 in a totally stereoselective process.
A pure sample of 11 could be obtained by crystallization
from hexane/ether at low temperature (-20 °C) but
formations, whereas 4 could be easily obtained from 511
by sulfinylation and further stereoselective reduction.
According to previously described methodology for the
synthesis of cyclic â-keto sulfoxides,8a,12 we attempted
direct sulfinylation of R′ enolate of 5,13 with menthyl
p-toluenesulfinate (6) (Scheme 3). Unfortunately treat-
ment of 5 with LDA followed by sulfinate 6 did not
provide the desired â-keto sulfoxides. The sodium or
magnesium enolates of 5 likewise failed to react. These
results are probably due to the low reactivity of both the
nucleophile (a doubly conjugated enolate) and the elec-
trophile (menthyl p-toluenesulfinate). We therefore tried
the more reactive, optically pure sulfinylating agents,
(4R,5S,(S)R)-4-methyl-5-phenyl-3-p-tolylsulfinyloxazoli-
din-2-one (7)14 and (S)-N-benzyl-N-(p-tolylsulfinyl)propi-
onamide (8).15 Sulfinylation of the lithium enolate of 5
with 7 afforded a 80:20 mixture16 of [5S,(S)R]-9a and
[5R,(S)R]-9b in a 68% combined yield. The ee of the
major isomer was 72%.17 The use of the sulfinylamide 8
(17) The enantiomeric excess was determined by using the chiral
shift reagent Eu(tfc)3 and confirmed in a further step by means of
Mosher’s esters of the hydroxy derivative 3.
(18) (a) Barros, D.; Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Maestro,
M. C. Tetrahedron Lett. 1992, 33, 2733. (b) Bueno, A. B.; Carren˜o, M.
C.; Garc´ıa Ruano, J . L.; Pen˜a, B.; Rubio, A.; Hoyos, M. A. Tetrahedron
1994, 50, 9355.
(19) Chromatographic purification of the hydroxy sulfoxides
4
(11) Gannon, W. F.; House, H. O. Organic Synthesis; Wiley: New
York, 1963; Collect. Vol. IV, p 539.
(12) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Pedregal, C.; Rubio, A. J .
Chem. Soc., Perkin Trans. 1 1989, 1335.
yielded 4-(p-tolylsulfinyl)-2-cyclopenten-1-one (12) (the corresponding
thioether was derived from compound 10), as a result of the hydrolysis
of the enol ether moiety and the dehydration of the carbinol.
(13) With regard to the regioselectivity of cyclopentenone deproto-
nation (R′ or γ) see: Liang Chen, Y.; Mariano, P. S.; Little, G. M.;
O’Brian, D.; Huesmann, P. L. J . Org. Chem. 1981, 46, 4643. Koreeda,
M.; Mislankar, S. G. J . Am. Chem. Soc. 1983, 105, 7203.
(14) Evans, D. A; Faul, M. M.; Colombo, J . J .; Basaha, J .; Clardy,
J .; Cherry, D. J . Am. Chem. Soc. 1992, 114, 5977.
(15) Garc´ıa Ruano, J . L.; Alonso, R.; Zarzuelo, M. M.; Noheda, P.
Tetrahedron: Asymmetry 1995, 6, 1133. Enantiomer (R)-8 is also
available using (+)-menthol as quiral auxiliary.
(16) The absolute configuration of 9a and 9b was established by
comparison of their NMR data with those of 2-sulfinylcyclopentanones
previously described; see ref 8b.
(20) (a) Poutsma, M. L.; Kartch, J . L. J . Am. Chem. Soc. 1967, 89,
6595. (b) Middleton, D. S.; Simpkins, N. S. Synth. Commun. 1989, 19,
21. (c) Dalla, V.; Pale, P. Tetrahedron Lett. 1992, 33, 7857.
(21) Maag, H.; Rydzewski, R. M. J . Org. Chem. 1992, 57, 5823.

Synthesis of Glycosidase Inhibitor Precursors
J . Org. Chem., Vol. 62, No. 7, 1997 2141
Sch em e 5
Sch em e 6
decomposition to 12 took place quickly at room temper-
ature. Thus, the iodohydrin was used directly without
further purification, and the yield of this step was not
determined.
trichloroacetyl imide 15a is formed by the reaction of the
carbinol with trichloroacetyl isocyanate. Methanolysis
of the imide group yields the carbamate 15b, detectable
by H1 NMR. The nucleophilic attack of the nitrogen on
the vinyl sulfone moiety took place through the favored
cis-cyclization process, giving rise to oxazolidinone 16.
The configurational integrity of the alkoxy and amino
stereogenic centers of 16 was further confirmed. In a
single additional step the treatment of 16 with 35% HCl
allowed the isolation of oxazolidinone 2 in 62% yield. The
keto sulfone resulting from the hydrolysis of the ketal
was not detected. The elimination of the sulfone took
place, presumably due to the stability of the resulting
conjugate enone.
Transformation of compound 11 into the epoxide 13
was effected by treatment with K2CO3 in 80% conversion.
The formation of 13 confirmed the trans disposition
between the iodine atom and the hydroxy group in 11.
Further treatment of 13 with a stronger base (NaH)
yielded vinyl sulfoxide 3. The transformation of 11 into
3 could be directly achieved by using 2 equiv of NaH.
Thus, 3 was isolated in a 60% overall yield from the
â-keto sulfoxide 9a . The (S) absolute configuration at
the hydroxylic center of 3 as well as its optical purity
1
(96%) were established by H-NMR of the R-methoxy-R-
(trifluoromethyl)phenylacetate (MTPA) esters. Both
(S2,R)-MTPA and (R2,R)-MTPA esters were prepared
from racemic 3. The differences observed in the chemical
shifts of the carbinol substituents in both diastereomers
allowed the configurational correlation according to the
model developed by Mosher and Dale.22 Thus, the
absolute configuration of 3 could be established as (2S)-
1,1-diethoxy-2-hydroxy-4-(p-tolylsulfinyl)cyclopenten-3-
one.
The structure of oxazolidinone 2 could be established
on the basis of its NMR parameters (see the Experimen-
tal Section), which are very similar to those of the tosyl
derivative analogous previously synthesized by Trost.6f
Con clu sion
Enantiomerically pure sulfinylcyclopentenones 9 readily
available from 3-ethoxycyclopent-2-en-1-one and the
sulfinylating agent (S)-N-benzyl-N-(p-tolylsulfinyl)pro-
pionamide (8), provide access to glycosidase inhibitor
precursors. Our synthesis features the preparation of
oxazolidinone (S,S)-2,25 using the highly diastereoselec-
tive DIBALH/ZnBr2 reduction of 9 as a key step. Trans-
formation of the resulting hydroxy sulfoxide into 2 occurs
uneventfully.
In order to obtain the cyclic carbamate present in 2,
an intramolecular Michael addition was required. Since
the sulfinyl group23 does not activate this process enough,
it was necessary to transform compound 3 into the
sulfone 14 (Scheme 6), which was quantitatively formed
by m-CPBA oxidation. Reaction of sulfone 14 with
trichloroacetyl isocyanate24 in the presence of K2CO3 and
addition of another equivalent of K2CO3 in MeOH/CH2-
Cl2, provided 16 as a 75:25 mixture of C-4 epimers.
Several steps are involved in this transformation. First,
Exp er im en ta l Section
(22) See: (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512. (b) Yamaguchi, S. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1983; Vol. 1, p 125. (c) Chan, T. H.; Nwe,
K. T. J . Org. Chem. 1992, 57, 6107.
(23) The reaction of 3 with trichloroacetyl isocyanate in the presence
of K2CO3 followed by addition of base in MeOH/CH2Cl2 failed to yield
the corresponding sulfinylcarbamate.
(5S,(S)S)-3-Eth oxy-5-(p-tolylsu lfin yl)cyclop en t-2-en -1-
on e (9). A solution of 341 mg (2.7 mmol) of 3-ethoxycyclopent-
2-en-1-one (5) in 7 mL of THF was added under argon to a
solution of 2.7 mmol of LDA in 7 mL of anhydrous THF at
(24) (a) Hirama, M.; Hioki, H.; Itoˆ, S. Tetrahedron Lett. 1988, 29,
3125. (b) Blas, J . de; Carretero, J . C.; Dom´ınguez, E. Tetrahedron Lett.
1994, 35, 4603.
(25) The use of the readily available (R)-8 (see ref 15) would give
access to (R,R)-2, which possesses the same stereochemistry as
mannostatin.

2142 J . Org. Chem., Vol. 62, No. 7, 1997
Bueno et al.
-78 °C over 20 min. The solution was stirred for 1 h at -78
°C. The enolate was added by cannula at the same temper-
ature over a solution of 1.63 g (5.4 mmol) of (+)-(S)-N-benzyl-
N-(p-tolylsulfinyl)propionamide (8) in 15 mL of anhydrous THF
over 2 min. After the mixture was stirred for 1 h, saturated
NH4Cl was added, and the mixture was allowed to reach rt.
The aqueous layer was extracted with CH2Cl2 (4 × 20 mL).
The organic layers were combined and dried over MgSO4. The
solvents were removed in vacuo, and the residue was purified
by chromatography (EtOAc/hexane 1:2) to give 293 mg of a
80:20 mixture of 9a /9b as a yellow solid (75% yield). Com-
pound 9a was isolated diastereomerically pure by repeated
recrystallizations from ether containing a drop of 1 N NaOH
ta n -1-on e Dieth yl Aceta l (13). Compound 11 was diluted
in 3 mL of CH3CN/THF (2:1), and 114 mg (0.82 mmol) of K2-
CO3 was added at rt. After 23 h, saturated Na2SO3 (5 mL)
was added, and the aqueous layer was extracted with CH2-
Cl2. The organic layer was dried over Na2SO4, and the solvents
were removed in vacuo. The residue was purified by chroma-
tography (EtOAc/hexane 1:3) to yield pure 13 (overall 65%
yield from 9a ): 1H NMR δ 7.62 and 7.35 (AA′BB′ system, 4H),
3.63 (m, 4H), 3.53 (m, 1H), 3.19 (m, 2H), 2.43 (s, 3H), 2.21 (m,
1H), 2.03 (m, 1H), 1.24 (t, J ) 7.0 Hz, 3H), 1.15 (t, J ) 7.0 Hz,
3H).
(2S,(S)S)-2-Hyd r oxy-4-(p-tolylsu lfin yl)cyclop en t-3-en -
1-on e Dieth yl Aceta l (3). A solution of 11 in 3 mL of THF
was added under argon to a suspension of 22 mg (0.92 mmol)
of NaH in 1 mL of THF at rt. After 15 min, the mixture was
quenched with saturated NH4Cl, extracted with CH2Cl2, and
dried over Na2SO4. The solvents were removed in vacuo, and
the compound was purified by chromatography (EtOAc/hexane
1:2), affording 71 mg of 3 as a white solid (60% yield from 9a ):
1
solution. 9a : [R]D ) -554° (c 1, CHCl3); H ΝΜR δ 7.49 and
7.33 (AA′BB′ system, 4H), 5.38 (t, J ) 1.1 Hz, 1H), 4.08 (m,
2H), 3.57 (dd, J ) 7.4, 3.1 Hz, 1H), 3.05 (ddd, J ) 18.0, 3.1,
1.1 Hz, 1H), 2.42 (s, 3H), 2.32 (ddd, J ) 18.0, 7.4, 1.1 Hz, 1H),
1.40 (m, 3H); 13C NMR δ 197.5, 189.8, 141.4, 138.6, 129.9 (2C),
123.7 (2C), 104.9, 68.3, 68.0, 25.1, 21.3, 13.9. 9b (from an 80:
20 mixture of 9a :9b): 1H NMR δ 7.47 and 7.30 (AA′BB′ system,
4H), 4.95 (m, 1H), 4.28 (m, 1H), 3.83 (m, 2H), 2.95-2.66 (m,
2H), 2.39 (s, 1H), 1.23 (m, 3H); 13C NMR δ 197.5, 189.4, 141.9,
138.6, 129.3 (2C), 125.2 (2C), 104.8, 68.3, 68.0, 27.3, 21.3, 13.9;
mp 129-131 °C; IR (CHCl3) 3000, 1680, 1590, 1380 cm-1. Anal.
Calcd for C14H16O3S: C, 63.61; H, 6.10; N, 0.00. Found: C,
63.53; H, 5.91; N, 0.03 (from the mixture 9a :9b).
1
[R]D ) -126° (c 0.66, CHCl3); mp 87-88 °C; H NMR δ 7.49
and 7.30 (AA′BB′ system, 4H), 6.43 (bs, 1H), 4.67 (d, J ) 9.1
Hz, 1H), 3.6-3.2 (m, 4H), 3.09 (d, J ) 9.1 Hz, 1H), 2.76 (m,
1H), 2.41 (s, 3H), 2.19 (m, 1H), 1.14 (t, J ) 7.0 Hz, 3H), 1,13
(t, J ) 7.0 Hz, 3H); 13C NMR δ 146.4, 141.8, 138.5, 135.9, 129.9
(2C), 124.8 (2C), 107.0, 78.8, 58.2, 57.3, 34.7, 21.4, 15.1, 15.0;
IR (CHCl3): 3600, 2990, 2910, 1220 cm-1; Anal. HRMS calcd
(1R,5S,(S)S)-3-E t h oxy-5-(p -t olylsu lfin yl)cyclop en t -2-
en -1-ol (4c). A solution of 100 mg (0.38 mmol) of 3-ethoxy-
5-(p-tolylsulfinyl)cyclopent-2-en-1-one (9a ) and 171 mg (0.76
mmol) of ZnBr2 in 4 mL of THF was stirred at rt under argon
for 1 h. This mixture was added to a solution of 0.95 mL (0.95
mmol) of DIBALH (1 M in hexane) in 4 mL of THF at -78 °C
over 20 min. After the mixture was stirred at this temperature
for 3 h, 1 mL of methanol was added. The mixture was allowed
to reach rt and was transferred to an Erlenmeyer flask
containing 60 mL of aqueous saturated potassium-sodium
tartrate and 60 mL of EtOAc. The two layers were stirred for
15 min and separated. The aqueous layer was extracted with
EtOAc (4 × 20 mL), and the organic layers were combined
and dried over Na2SO4. After removal of the solvents in vacuo,
120 mg of 4c as a yellow oil was obtained: 1H NMR δ (from
the crude mixture) 7.86 and 7.35 (AA′BB′ system, 4H), 4.92
(m, 1H), 4.67 (m, 1H), 3.87 (m, 3H), 3.17 (m, 1H), 2.50 (m,
1H), 2.45 (s, 3H), 1.30 (t, J ) 7.0 Hz, 3H). This mixture was
used without purification.
(1S,5S,(S)S)-3-E t h oxy-5-(p -t olylsu lfin yl)cyclop en t -2-
en -1-ol (4t). A solution of 100 mg (0.38 mmol) of 3-ethoxy-
5-(p-tolylsulfinyl)cyclopent-2-en-1-one (9a ) was added to a
solution of 1.33 mL (1.33 mmol) of DIBALH (1 M in hexane)
in 4 mL of THF at -78 °C. After the mixture was stirred for
4 h, 1 mL of methanol was added, and the mixture was allowed
to reach rt. The treatment of the mixture was performed as
previously described for 4c in the DIBALH/ZnBr2 reduction,
affording 4t as a yellow oil: 1H NMR δ (from the crude
mixture) 7.50 and 7.30 (AA′BB′ system, 4H), 5.16 (m, 1H), 4.55
(m, 1H), 3.77 (q, J ) 7.0 Hz, 2H), 3.20 (ddd, J ) 9.0, 5.5, 3.6
Hz, 1H), 2.73 (m, 1H), 2.41 (s, 3H), 2.31 (m, 1H), 1.26 (t, J )
7.0 Hz, 3H).
(2R,3S,4S,(S)S)-3-h yd r oxy-2-iod o-4-(p-tolylsu lfin yl)cy-
clop en ta n -1-on e Dieth yl Aceta l (11). The crude mixture
of 4c was diluted in 4 mL of a 1:1 mixture of CH2Cl2/ethanol
at -20 °C, and 102 mg (0.46 mmol) of NIS was added in small
portions with stirring. After 10 min, a saturated solution of
Na2SO3 was added dropwise until decoloration occurred, and
the mixture was allowed to warm to rt. The solvents were
removed in vacuo, and the mixture was dissolved in CH2Cl2,
washed with saturated NaHCO3, and concentrated, affording
11. Compound 11 was used without further purification: 1H
NMR δ 7.56 and 7.32 (AA′BB′ system, 4H), 4.57 (ddd, J ) 12.0,
6.3, 1.3 Hz, 1H), 4.24 (t, J ) 1.3 Hz, 1H), 4.08 (d, J ) 12 Hz,
1H), 3.94 (dq, J ) 9.2, 7.1 Hz, 2H), 3.62 (m, 1H), 3.49 (q, J )
7.0 Hz, 2H), 2.95 (ddd, J ) 15.4, 4.9, 2.0 Hz, 1H), 2.41 (s, 3H),
2.06 (dd, J ) 15.4, 11.7 Hz, 1H), 1.27 (t, J ) 7.0 Hz, 3H), 1.21
(t, J ) 7.0 Hz, 3H); 13C NMR δ 141.2, 139.7, 129.7 (2C), 124.1
(2C), 109.3, 79.1, 76.3, 64.8, 58.5, 27.0, 21.2, 15.1, 14.6.
(2S,3R,4S,(S)S)-2,3-Ep oxy-4-(p-tolylsu lfin yl)cyclop en -
for C16H22O4S 310.1239, found 310.1233. Calcd for C16H22-
O4S: C, 61.91; H, 7.15; N, 0.00. Found: C, 62.00; H, 7.35; N,
0.08.
P r oced u r e for P r ep a r a tion of MTP A Ester s. To a
solution of 15 mg (0.05 mmol) of 3 and 12.4 mg (0.10 mmol) of
DMAP in 3 mL of CH2Cl2 was added 0.015 mL (0.083 mmol)
of (R)-MTPACl, and the mixture was stirred for 1 h at rt. The
reaction was quenched with water (1 mL) and Et2O (3 mL)
and stirred for 15 min. The solution was washed with 1 N
HCl (4 mL), 1 N NaOH (4 mL), and brine and dried over
MgSO4. The solvent was removed in vacuo, and the corre-
sponding MTPA ester was obtained and characterized without
further purification (80% yield): 1H NMR δ (2S,R)-MTPA ester
7.57-7.27 (m, 9H), 6.61 (ABX system, J ) 2.3, 1.2 Hz, 1H),
5.68 (d, J ) 2.8 Hz, 1H), 3.61-3.13 (m, 4H), 3.50 (s, 3H), 2.48
and 2.36 (ABX system, J ) 15.3, 1.2 Hz, 2H), 2.41 (s, 3H),
1.08 (t, J ) 7.0 Hz, 3H), 1.05 (t, J ) 7.0 Hz, 3H) (2R,R)-MTPA
ester 7.57-7.27 (m, 9H), 6.48 (ABX system, J ) 2.3, 1.2 Hz,
1H), 5.81 (d, J ) 2.8 Hz, 1H), 3.61-3.13 (m, 4H), 3.56 (s, 3H),
2.48 and 2.36 (ABX system, J ) 15.3, 1.2 Hz, 2H), 2.41 (s,
3H), 1.08 (t, J ) 7.0 Hz, 3H), 1.05 (t, J ) 7.0 Hz, 3H).
(2S)-2-H yd r oxy-4-(p -t olylsu lfon yl)cyclop e n t -3-e n -1-
on e Dieth yl Aceta l (14). To a solution of 100 mg (0.32 mmol)
of vinyl sulfoxide 3 in 3 mL of CH2Cl2 at 0 °C was added a
solution of 110 mg (0.32 mmol) of m-CPBA (50% aqueous) in
5 mL of CH2Cl2. After the mixture was stirred for 15 min, 1
mL of a saturated solution of Na2SO3 was added, and the
mixture was warmed to rt over 15 min. The organic layer was
washed with saturated aqueous NaHCO3 and dried over Na2-
SO4, and the solvent was removed in vacuo, yielding 105 mg
of 14 as a colorless oil (95% yield): [R]D ) -57° (c 0.3, CHCl3);
1H NMR δ 7.76 and 7.35 (AA′BB′ system, 4H), 6.52 (m, 1H),
4.69 (d, J ) 9.4 Hz, 1H), 3.52 (m, 4H), 3.05 (d, J ) 9.4 Hz,
1H), 2.86 (m, 1H), 2.52 (m, 1H), 2.45 (s, 3H), 1.14 (t, J ) 7.0
Hz, 3H), 1.13 (t, J ) 7.0 Hz, 3H); 13C NMR δ 144.9, 142.5,
140.5, 135.4, 129.9 (2C), 128.2 (2C), 107.5, 78.8, 58.5, 57.3, 21.6,
15.1, 15.0; IR (CHCl3) 3540 (b), 3000, 2980, 1220 cm-1
.
4,4-Diet h oxy-6-(p -t olylsu lfon yl)cyclop en t a n e[5,4-d ]-
(3a S,6a S)-oxa zolid in -2-on e (16). To a solution of 100 mg
(0.31 mmol) of 14 in 1 mL of anhydrous THF was added 48
mg (0.34 mmol) of K2CO3. After the solution was stirred for
30 min, 0.045 mL (0.37 mmol) of trichloroacetyl isocyanate was
added. The mixture was stirred overnight at rt. The solvent
was removed in vacuo, the residue was diluted with 2 mL of
a 1:1 mixture of CH2Cl2/methanol, and 48 mg (0.34 mmol) of
K2CO3 was added. The mixture was stirred for 7 h, and then
CH2Cl2 was added and the solution was washed with saturated
aqueous NH4Cl. The organic layers were combined and dried
over MgSO4 and concentrated in vacuo to give 108 mg of 16
as a 72:28 epimeric mixture (95% yield): mp 184-185 °C; 1H

Synthesis of Glycosidase Inhibitor Precursors
J . Org. Chem., Vol. 62, No. 7, 1997 2143
NMR δ (diastereomeric mixture) 7.77 and 7.41 (AA′BB′ system,
1.2H), 7.76 and 7.40 (AA′BB′ system, 2.8H), 5.78 (bs, 0.7H),
5.12 (bs, 0.3H), 4.82-4.48 (m, 2H), 3.72-3.18 (m, 5H), 2.49
(s, 0.3H), 2.34-2.19 (m, 2H), 1.20 (t, J ) 7.0 Hz, 2.2H), 1.15
(t, J ) 7.0 Hz, 1.6H), 1.09 (t, J ) 7.0 Hz, 2.2H); 13C NMR δ
(diastereomeric mixture) 157.8, 157.3, 145.8, 145.5, 135.8,
134.4, 130.4, 130.2, 128.3, 106.3, 105.9, 82.4, 80.4, 68.6, 63.6,
59.3, 59.1, 57.8, 56.3, 54.6, 53.8, 32.8, 30.8, 30.7, 21.6, 15.1,
14.9; IR (CHCl3) 3420, 2990, 1770, 1150 cm-1; HRMS calcd
for C17H23NO6S 369.1246, found 369.1234.
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (Grants PB92-161 and
PB93-257) and Comunidad Auto´noma de Madrid
(AE00144/94) for financial support and Dr. Steve Wen-
globsky for English language corrections. One of us
(M.M.Z.) thanks Ministerio de Educacio´n y Ciencia for
a fellowship.
4-Oxocyclop e n t -5-e n [5,4-d ]-(3a S ,6a S )-oxa zolid in -2-
on e (2). A solution of 32 mg (0.09 mmol) of 16 in 2 mL of
35% HCl was stirred at rt for 4 h. The mixture was diluted
with CH2Cl2, washed with saturated aqueous NaHCO3, and
dried over Na2SO4. Solvents were removed in vacuo, and
chromatography of the residue (EtOAc/hexane 1:1) gave 7.5
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of compounds 2, 3, 9a , 12, 14, 16, the MTPA-esters of
3, and the acetyl derivate of 11 (8 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.
1
mg of 2 (62% yield): [R]D ) -140° (c 0.2, CHCl3); H NMR δ
7.69 (dd, J ) 6.0, 2.1 Hz, 1H), 6.57 (bs, 1H), 6.49 (dd, J ) 6.0,
0.8 Hz, 1H), 4.82 (m, 2H); 13C NMR δ 199.4, 160.2, 157.7, 135.7,
74.35, 54.9; IR (CHCl3): 3400, 2990, 2860, 2400, 1730, 1200
cm-1; HRMS calcd for C6H5NO3 139.0260, found 139.0269.
J O961774U