Opening of thiiranes: Preparation of orthogonal protected 2-thioglyceraldehyde

Article abstract of DOI:10.1021/jo001392v

Treatment of acrolein diethyl acetal sulfide 8 with methanesulfenyl bromide at low temperature results in an efficient thiirane ring opening to a halo disulfide 9. The bromine in this halo disulfide is easily substituted by silver acetate, sodium azide, sodium iodide, and silver nitrate. Treatment of 9 with tetrabutylammonium acetate yields a novel dehydrohalogenation product 12. Silica gel converts bromide 9 into a disulfide-substituted version of acrolein 15. The orthogonal-protected version of 2-thioglyceraldehyde 13 can be deprotected to a useful form of this aldehyde.

Full text of DOI:10.1021/jo001392v

910
J . Org. Chem. 2001, 66, 910-914
Op en in g of Th iir a n es: P r ep a r a tion of Or th ogon a l P r otected
2-Th ioglycer a ld eh yd e
Michael G. Silvestri† and Chi-Huey Wong*
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
wong@scripps.edu
Received September 19, 2000
Treatment of acrolein diethyl acetal sulfide 8 with methanesulfenyl bromide at low temperature
results in an efficient thiirane ring opening to a halo disulfide 9. The bromine in this halo disulfide
is easily substituted by silver acetate, sodium azide, sodium iodide, and silver nitrate. Treatment
of 9 with tetrabutylammonium acetate yields a novel dehydrohalogenation product 12. Silica gel
converts bromide 9 into a disulfide-substituted version of acrolein 15. The orthogonal-protected
version of 2-thioglyceraldehyde 13 can be deprotected to a useful form of this aldehyde.
In tr od u ction
produces a halo disulfide. The easy transformation of the
halo disulfide into a fully protected version of 2-thioglyc-
eraldehyde, and its conversion to a usable form of
2-thioglyceraldehyde, is described. We also report on the
preparation of additional analogues, and describe some
of the chemistry that we investigated.
The introduction of sulfur as a heteroatom in many
carbohydrates has shown to be an effective technique for
imparting significant biological activity.1 Their function
as enzyme inhibitors, and the antibacterial, antineoplas-
tic, and antiviral activity for a number of sulfur analogues
of deoxyribonucleosides is notable.2,3 It is surprising,
given the recent flurry of synthetic activity to prepare
derivatives of 4-thio-2-deoxyribose,3 that a preparation
of the simplest member of the thiocarbohydrate family,
2-thioglyceraldehyde, has not been reported in the lit-
erature. Nearly 30 years ago, there were, however, a few
reports of its use in the literature, one reporting antitu-
mor activity in animal test studies.4 With respect to the
above, and in light of our interest in enzyme-catalyzed
reactions in organic chemistry, we required an efficient
procedure for the preparation of an orthogonal-protected
2-thioaldehyde derivative.
Resu lts a n d Discu ssion
Our initial strategy, shown in Scheme 1, focused on
preparation of this molecule’s framework protected as
acetal and acetate,5 with subsequent incorporation of the
thiol functionality at position-2, by either Mitsunobu
conditions or direct tosylate displacement. Unfortunately,
neither of these straightforward procedures produced any
reaction when thiolacetic acid, ziram, or triphenylsi-
lanethiol was used in a Mitsunobu reaction6 with alcohol
2 or their lithium salts were used as nucleophiles for
direct tosylate substitution of 3.
Alternatively, the Mitsunobu-like intermediate sug-
gested in the epoxide to chlorohydrin method of Palumbo
et al.7 was thought to present an alternate approach for
introduction of the thiol functionality, as shown in
Scheme 2. Unfortunately all attempts to directly replace
the triphenylphosphene oxide of presumed intermediate
5, by a sulfur nucleophile, failed. The use of strong
nucleophiles such as lithium benzylmercaptoate resulted
in halide substitution only. When either thiolacetic acid
with or without triethylamine or triphenylsilanethiol/
triethylamine was used as nucleophile, only chlorohydrin
6 was produced. Surprisingly, however, when triphenyl-
silanethiol was used as a nucleophile without triethyl-
amine, the triphenylsilyl-protected chlorohydrin 7 was
formed in high yield, accompanied by triphenylphosphine
sulfide.
In this paper, we report an efficient new procedure for
the thiirane ring opening, a procedure which directly
† Current address: Department of Chemistry and Biochemistry,
California Polytechnic State University, San Luis Obispo, CA 93407.
(1) Witczak, Z. J . Curr. Med. Chem. 1999, 6, 165-178.
(2) Zoller, H. Handbook of Enzyme Inhibitors; Wiley/VCH: Wein-
heim, 1999; Part A/1+2, Part B/1+2. Hideya, Y.; Hindsgaul, O.; Palcic,
M. M. J . Am. Chem. Soc. 1992, 114, 5891-5892. Durieux, I.; Martel,
M. B.; Got, R. Glycoconjugate J . 1990, 7, 183-192. Baubichon-Cortay,
J .; Broquet, P.; George, P.; Louisot, P. Glycoconjugate J . 1989, 6, 115-
127.
(3) Kim, H. O.; J eong, L. S.; Lee, S. N.; Yoo, S. J .; Moon, H. R.; Kim,
K. S.; Chun, M. W. J . Chem. Soc., Perkin Trans. 1 2000, 9, 1327-
1329. Wang, Y.; Inguaggiato, G.; J asamai, M.; Shah, M.; Hughes, D.;
Slater, M.; Simons, C. Bioorg. Med. Chem. 1999, 7, 481-487. Wirsch-
ing, J .; Voss, J . Eur. J . Org. Chem. 1938, 3, 691-696. Inguaggiato, G.
Hughes, D.; De Clercq, E.; Balzarini, J .; Simons, C. Antiviral Chem.
Chemother. 1999, 10, 241-249. Messini, L.; Tiwari, K. N.; Montgomery,
J . A.; Secrist, J . A., III. Nucleosides Nucleotides 1999, 18, 683-685.
J eong, L. S.; Moon, Hyung, R.; Yoo, S. J .; Lee, S. N.; Kim, H.-D.; Chun,
M. W. Nucleosides Nucleotides 1999, 18, 571-572. Inguaggiato, G.;
J asamai, M.; Smith, J . E.; Slater, M.; Simons, C. Nucleosides Nucle-
otides 1999, 18, 457-467. Wang, Y.; Inguaggiato, G.; J asamai, M.;
Shah, M.; Hughes, D.; Slater, M.; Simons, C. Bioorg. Med. Chem. 1999,
7, 481-487. Yoshimura, Y.; Endo, M.; Miura, S.; Sakata, S. J . Org.
Chem. 1999, 64, 7912-7920. Falconer, R. A.; J ablonkai, I.; Toth, I.
Tetrahedron Lett. 1999, 40, 8663-8666.
Electrophilic or nucleophilic thiirane ring opening
presents a potentially expedient route to a protected
(5) Ishihara, K.; Kurihara, H.; Yamamoto, H. J . Org. Chem. 1993,
58, 3791-3793.
(6) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119-3122. Rollin,
P. Tetrahedron Lett. 1986, 27, 4169-4170. Besson, T.; Neirabeyeh, M.
A.; Viaud, M.-C.; Rollin, P. Synth. Commun. 1990, 1631-1639. Gareau,
Y.; Brittain, J . Tetrahedron Lett. 1993, 34, 3363-3366.
(7) Palumbo, G.; Ferreri, C. Caputo, R. Tetrahedron Lett. 1983, 24,
1307-1310.
(4) Stevenes, J . P., and Co., Inc. GB Patent 01,092, 961, 1967; Chem.
Abstr. 1968, 68, 22699, Apple, M. A.; Greenberg, D. M. Cancer
Chemother. Rep. 1969, 53, 195-198. Broome, J . D.; J eng, M. W. J .
Exp. Med. 1973, 138, 574-592.
10.1021/jo001392v CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/11/2001

Opening of Thiiranes
J . Org. Chem., Vol. 66, No. 3, 2001 911
Sch em e 1a
Sch em e 4
a
Reagents and conditions: (b) AcCl, collidine, CH2Cl2, -78 °C,
3 h; (c) TsCl, DMAP, CH2Cl2, rt/5 days.
Sch em e 5a
Sch em e 2
a
Reagents and conditions: (b) NaI, acetone, reflux, 90 min; (c)
NaN3, DMSO, 17 h; (d) AgOAc, ether, 72 h; (e) AgNO3, ether, 72
h; (f) Bu4NOAc, THF, reflux, 45 min, quantitative; (g) silica gel.
that the thioglycoside coupling reagent, DMTST,9 expedi-
ently opened the thiirane without disturbing the acetal
protecting group, as shown in Scheme 4. Unfortunately,
all attempts to inhibit the incorporation of methyl sulfide
from the reagent itself and introduce an alternate nu-
cleophile were unsuccessful. Whereas triphenylsilanthiol
was not a competitive nucleophile, stronger nucleophiles
such as p-methoxybenzene and lithium trimethylsil-
anoate destroyed the reagent, returning the thiirane
unchanged.
Sch em e 3
We are pleased to report that methanesulfenyl bro-
mide, a reagent easily prepared by treatment of methyl
disulfide with bromine, efficiently opens thiirane 8,
producing a versatile brominated disulfide 9, which can
be converted to a fully protected version of 2-thioglycer-
aldehyde, as shown in Scheme 5. The bromine in 9 can
easily be substituted by iodide,10 azide,11 nitrate,12 and
acetate.13 Additionally, hydrogen bromide can be elimi-
nated with tetrabutylammonium acetate to produce a
2-thioglyceraldehyde as shown in Scheme 3. Unfortu-
nately, many of the methods that are available are
incompatible with an aldehyde or protected aldehyde
functional group.8 Lithium hydroxide and lithium tri-
methylsilanoate were unreactive nucleophiles toward
thiirane 8, while 2-nitrobenzyl alcohol and phosphate
gave only polymerization. Electophilic reagents such as
trimethylsilyl acetate and CAN gave respectively, no
reaction and polymerization. We were encouraged to find
(9) Dasgupta, F.; Garegg, P. J . Carbohydrate Res. 1988, 177, c13-
c17.
(10) Easton, C. J ..; Merrett, M. C. Tetrahedron 1997, 53, 1151-1156.
(11) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413-414.
(12) Castedo, L.; Marcos, C. F.; Tojo, G. Synth Commun. 1995, 25,
1729-1739.
(13) Balsamo, A.; Benvenuti, M.; Lapucci, A.; Macchia, B.; Nencetti,
S.; Rossello, A.; Macchia, F.; Domiano, P.; Dradi, E. J . Org. Chem. 1991,
56, 2148-2153. Rosenau, T.; Habicher, W. D. J . Prakt. Chem./ Chem.-
Ztg. 1996, 338, 647-653.
(8) Iranpoor, N.; Owji, J . Tetrahedron Lett. 1991, 47, 149-154.
Sander, M. Chem. Rev. 1966, 66, 297-339.

912 J . Org. Chem., Vol. 66, No. 3, 2001
Silvestri and Wong
Sch em e 6a
ratio between methyl disulfide and bromine, has been
used with silver triflate as a coupling reagent for
carbohydrates.19 When it is preformed, then administered
to the thiosugar, a large excess, 6-10 equiv, of the
reagent is required to achieve successful coupling. This
is in contrast to the procedure where silver triflate is
added directly to the carbohydrate and methanesulfenyl
bromide, where a slight excess of the reagent is required.
We suspect that the equilibrium between methyl disul-
fide and bromine needs to be pushed forward with the
3:1 ratio, and suspect that for carbohydrate couplings,
this ratio may be advantageous.
Su m m a r y
a
In summary we have shown that the methanesulfenyl
bromide method of opening thiiranes, is highly successful
for the introduction of a sulfur atom next to the aldehyde
functional group, as demonstrated here in a synthesis of
an orthogonal protected version of the smallest member
of the thiosugar family, 2-thioglyceraldehyde. The com-
bined functionality of the R-thioaldehyde is one that has
presented itself only a few times in the chemical litera-
ture.20 We suspect that this method will find general
applicability in the future, as we have begun to observe
success with other thiiranes. We are continuing to
investigate the generality of this procedure and will
report on that soon. Additionally, we suspect that the
differentially substituted molecules we have reported
here, will find applicability in synthetic applications. Our
own efforts to utilize these materials in enzymatic
reactions are underway.
Reagents and conditions: (b) LiAlH4, ether, rt, 15 h; (c)
NaOCH3/CH3OH, rt, 4 h; (d) H2O, HCl, 50 °C, 4 h.
novel vinyl disulfide 12. Attempted purification of bro-
mide 9 on silica gel produces predominantly a disulfide
version of acrolein 15, arising from hydrolysis and
dehydrohalogenation. An analytical sample of bromide
9 is, however, effectively received by chromatography on
Florisil.
The orthogonal-protected 2-thioglyceraldehyde deriva-
tive 13 can be deprotected by acetate hydrolysis, giving
alcohol 16, or alternatively the disulfide and acetate can
be removed simultaneously at room temperature with
lithium aluminum hydride in ether,14 giving 2-thioglyc-
eraldehyde diethylacetal 17; Scheme 6. When this reduc-
tion is performed in refluxing THF, and to a lesser extent
in refluxing ether, an alternate reduction product is
formed that appears to incorporate aluminum. Addition-
ally, if the hydride reduction reaction is quenched with
water, then acidified, a significant amount of mixed
disulfide is formed. The quench is favorably accomplished
with cold saturated sodium hydrogen sulfate. Magnesium
metal in methanol is also an effective reagent for the
acetate hydrolysis and, to a lesser extent, for the disulfide
to thiol conversion.15 This reagent system produces first
alcohol 16, which then forms product 17 contaminated
by mixed disulfides. When 17 is heated to 50 °C in water
with the pH adjusted to 1, the acetal is quickly cleaved.16
Although the formation of the aldehyde can be detected
Exp er im en ta l Section
Gen er a l Meth od s. Dichloromethane was distilled from
CaH2. THF and diethyl ether were distilled from sodium metal
and benzophenone. Commercially available anhydrous ac-
etone, CH3OH, and DMSO were used. Molecular sieves (4 Å),
obtained as an activated powder (average particle size, 2-3
µm), were further activated overnight, at 120 °C. Reagents of
commercial quality were purchased and used without further
purification unless otherwise stated. Column chromatography
was performed on silica gel 60 Geduran (35-75 µm, EM
Science) and Florisil (TLC grade). 1H and 13C NMR spectra
were recorded in CDCl3 at 250 and 62.9 MHz, respectively,
using TMS and CDCl3 as respective references. Mass spectra
were obtained as gc/ms, electrospray and MALDITOF. High-
resolution mass spectra were obtained at The Scripps Research
Institute and at the Mass Spectrometry Facility in the Depart-
ment of Chemistry, University of California, Santa Barbara,
CA. Elemental analyses were performed in the Chemistry
Department at The Scripps Research Institute.
Meth a n esu lfen yl Br om id e. Into an oven-dried 5 mL
volumetric flask containing 2 mL of anhydrous 1,2-dichloro-
ethane was added bromine (0.9008 g, 5.636 mmol) followed
by freshly distilled methyl disulfide (1.5 mL, 1.57 g, 16.66
mmol). The remaining volume was adjusted to 5 mL with more
anhydrous 1,2-dichloroethane. The flask was sealed from air
and light and then stirred for 4 h. The resultant 2.25 M
solution was used immediately, or successfully stored at -30
°C for up to 1 month, without any appreciable change in
reactivity.
1
by H NMR, attempts to isolate this material generates
a highly insoluble higher order compound.17
For a clean opening of the thiirane ring, we have found
that the methanesulfenyl bromide is best prepared with
a 3:1 ratio of methyl disulfide and bromine. This reagent
can be stored without a noticeable decrease in reactivity
for a period of 4 weeks. When a 1:1 ratio is used, bromide
9 is produced along with a product that appears to arise
from the direct opening of the thiirane by molecular
bromine.18 Methanesulfenyl bromide, produced as a 1:1
(14) Nishimura, H.; Yamauchi, O.; Takamatsu, H.; Chem. Pharm.
Bull. 1964, 12, 1004. Eliel, E. L.; Rao, V. S.; Smith, S.; Hutchins, R.
O. J . Org. Chem. 1975, 40, 524-526.
(15) Sridhar, M.; Vadivel, S. K.; Bhalerao, U. T. Synth. Commun.
1997, 27, 1347-1350.
(16) Chou, W.-C.; Chen, L.; Fang, J .-M.; Wong, C.-H. J . Am. Chem.
Soc. 1994, 116, 6191-6194.
1-Br om o-3,3-dieth oxy-2-(m eth yldith io)pr opan e (9). Un-
der an atmosphere of argon, thiirane 821 (0.1985 g, 1.223 mmol)
was added to a dry 25 mL round-bottom flask containing a
(17) 2-Thioglyceraldehyde is listed in the Aldrich Rare Chemicals
catalog. Their material behaves identically to our 18. The elemental
analysis is consistent for C3H6O2S (Anal. Calcd for C3H6O2S: C, 33.95;
H, 5.70. Found: C, 33.92; H, 5.59), and the material is insoluble in
CDCl3, acetone-d6, DMSO-d6, and D2O.
(19) Reference 9.
(20) Bourdon, F.; Ripoll, J .-L.; Vallee, Y. Tetrahedron Lett. 1990,
43, 6183-6184. Giles, H. G.; Marty, R. A.; De Mayo, P. Can. J . Chem.
1976, 54, 534. Yoshida, J .-I.; Nakatani, S.; Isoe, S. J . Org. Chem. 1993,
58, 4855-4865.
(18) Stewart, J . M.; Cordts, H. P. J . Am. Chem. Soc. 1952, 74, 5880.
Epstein, G. Y.; Usov, I. A.; Ivin, S. Z. Zh. Obshch. Khim. 1964, 34,
1948.

Opening of Thiiranes
J . Org. Chem., Vol. 66, No. 3, 2001 913
magnetic stir-bar and septum. Anhydrous dichloromethane (10
mL) was added followed by 1,1,3,3-tetramethylurea (0.18 mL,
0.175 g, 1.50 mmol) and powdered 4 Å molecular sieves (1.0
g). The solution was cooled to -78 °C, then treated by the
dropwise addition of methanesulfenyl bromide (0.66 mL, 1.485
mmol, 2.25 M). The solution was allowed to stir for an
additional 25 min at -78 °C, warmed to 0 °C, filtered through
a pad of diatomaceous earth, then concentrated at the rotary
evaporator. The resulting oil was dissolved in ether (10 mL)
and water (15 mL) and then extracted twice with 20 mL of
ether. The combined organic layer was then washed twice with
water (15 mL), once with brine (10 mL), dried (MgSO4), and
concentrated to 0.330 g (93%) of the desired product 9, as a
colorless oil. An analytical sample was obtained by purification
on Florisil (5% EtOAc/95% hexane eluent): 1H NMR (CDCl3)
δ 4.74 (d, J ) 4.4 Hz, 1H), 3.81-3.55 (m, 6H), 3.22-3.16 (m
1H), 2.46 (s, 3H), 1.26 (t, J ) 6.9 Hz, 3 H), 1.24 (t, J ) 6.9 Hz,
3 H); 13C NMR (CDCl3) δ 102.32, 64.24, 64.12, 57.77, 32.53,
23.71, 15.27, 15.1; mass spectrum (M)+ m/e 288/290; HRMS
calcd for C8H17BrO2S2 (M)+ m/e 287.9853, measured 287.9855.
1,1-Dieth oxy-3-iodo-2-(m eth yldith io)-pr opa n e (10). Into
a dry 25 mL round-bottom flask under argon, was combined
the bromide 9 (0.0257 g, 0.0888 mmol), sodium iodide (0.038
g, 0.254 mmol) and 5 mL acetone. This mixture was refluxed
1.5 h, cooled, and concentrated. The oil was diluted with water
(10 mL) then extracted twice with 15 mL ether. The organic
layer was washed once with water (10 mL), once with brine
(10 mL), dried (MgSO4), and concentrated to 0.026 g (87%) of
the desired product 10, as a colorless oil. An analytical sample
was obtained by purification on silica gel (3% EtOAc/97%
hexane eluent): 1H NMR (CDCl3) δ 4.70 (d, J ) 4.4 Hz, 1H),
3.81-3.57 (m, 6H), 3.09-3.02 (m 1H), 2.46 (s, 3H), 1.26 (t, J
) 6.9 Hz, 3 H), 1.24 (t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3) δ
103.35, 64.18, 64.12, 57.44, 23.74, 15.30, 15.18, 6.80; mass
spectrum (M)+ m/e 336; HRMS calcd for C8H17IO2S2 (M)+ m/e
335.9715, measured 335.9720. Anal. Calcd for C8H17IO2S2: C,
28.54; H, 5.10. Found: C, 28.34; H, 5.39.
1-Azido-3,3-dieth oxy-2-(m eth yldith io)pr opan e (11). Into
a dry 25 mL round-bottom flask under argon was combined
the bromide 9 (0.156 g, 0.539 mmol) and sodium azide (0.0393
g, 0.6045 mmol) with anhydrous DMSO (8 mL). The mixture
was sealed from the air and stirred for a period of 17 h. Water
(5 mL) was added, and then the mixture was extracted three
times with ether (10 mL). The organic layer was washed twice
with water (10 mL) and once with brine (10 mL), dried
(MgSO4), and concentrated to 0.130 g (96%) of the desired
product 11, as a colorless oil. An analytical sample was
obtained by purification on silica (50% CH2Cl2/50% hexane
eluent): 1H NMR (CDCl3) δ 4.61 (d, J ) 4.8 Hz, 1H), 3.80-
3.54 (m, 6H), 3.07-3.02 (m 1H), 2.46 (s, 3H), 1.24 (t, J ) 6.9
Hz, 6 H); 13C NMR (CDCl3) δ 102.32, 64.09, 63.33, 55.27, 50.50,
23.71, 15.10; mass spectrum (M)+ m/e 251. Anal. Calcd for
C8H17N3O2S2: C, 38.22; H, 6.82; N, 16.72. Found: C, 38.52;
H, 6.60; N, 16.57.
combined the bromide 9 (1.60 g, 5.532 mmol), silver acetate
(1.351 g, 8.094 mmol), and ether (10 mL). The mixture was
stirred under argon for 3 days, allowing the mixture to go
completely dry.22 Ether (20 mL) was added along with ac-
tivated charcoal. The mixture was filtered through diatoma-
ceous earth and then concentrated to 1.20 g (81%) of the
desired product 13, as a colorless oil. An analytical sample
was obtained by purification on silica (15% EtOAc/85% hex-
ane eluent): 1H NMR (CDCl3) δ 4.62 (d, J ) 5.1 Hz, 1H),
4.47 (dd, J ) 11.7, 5.1 Hz, 1H), 4.32 (dd, J ) 11.7, 6.5 Hz, 1H)
3.79-3.50 (m, 4H), 3.23-3.16 (m 1H), 2.43 (s, 3H), 2.09 (s,
3H), 1.24 (t, J ) 6.9 Hz, 3 H), 1.22 (t, J ) 6.9 Hz, 3 H); 13C
NMR (CDCl3) δ 170.67, 102.07, 63.50, 63.12, 62.71, 54.18,
23.80, 20.80, 15.06; mass spectrum (M)+ m/e 268; HRMS calcd
for C10H20O4S2 (M)+ m/e 268.0803, measured 268.0800. Anal.
Calcd for C10H20O4S2: C, 44.75; H, 7.51. Found: C, 44.44; H,
7.66.
3,3-Dieth oxy-2-(m eth yld ith io)p r op a n -1-ol Nitr a te (14).
Into a dry 25 mL round-bottom flask under argon were
combined the bromide 9 (0.0407 g, 0.1407 mmol), acetone (3
mL), water (0.25 mL), and silver nitrate (0.0294 g, 0.173
mmol). The mixture was stirred under argon for a period of 3
days, concentrated, and then diluted with ether (20 mL). The
ether layer was treated with MgSO4 and then activated
charcoal. After filtration through diatomaceous earth and
concentration, 0.030 g (80%) of the desired product 14 was
obtained, as a colorless oil. An analytical sample was obtained
by purification on silica (25% EtOAc/75% hexane eluent: 1H
NMR (CDCl3) δ 4.89 (dd, J ) 11.7, 5.8 Hz, 1H), 4.70 (dd, J )
11.7, 7.1 Hz, 1H), 4.64 (d, J ) 4.4 Hz, 1H), 3.80-3.47 (m, 4H),
3.27-3.20 (m 1H), 2.46 (s, 3H), 1.24 (t, J ) 6.9 Hz, 3 H), 1.23
(t, J ) 6.9 Hz, 3 H); 13C NMR (CDCl3) δ 102.29, 71.12, 64.42,
63.68, 62.71, 53.06, 15.09; mass spectrum (M)+ m/e 271; HRMS
calcd for C8H17NO5S2 (M)+ m/e 271.0548, measured 271.0544.
Anal. Calcd for C8H17NO5S2: C, 35.41; H, 6.31; N, 5.16.
Found: C, 35.60; H, 6.51; N, 4.78.
3,3-Dieth oxy-2-(m eth yld ith io)-p r op a n -1-ol (16). Into a
dry 25 mL round-bottom flask under argon were combined
acetate 13 (0.2005 g, 0.747 mmol) and 10 mL of dry methanol.
Two drops of a 25% solution of NaOCH3/CH3OH were added,
and the resultant mixture was stirred for 4 h at room
temperature. The volatiles were removed, and then ether (10
mL) and NaHSO4 (10 mL, saturated) were added. The result-
ant was extracted twice with ether (15 mL). The organic layer
was washed twice with water (10 mL), once with brine (10
mL), dried (MgSO4) and concentrated to 0.162 g (96%) of the
desired product 16, as a colorless oil. An analytical sample was
obtained by purification on silica (30% EtOAc/70% hexane
eluent): 1H NMR (CDCl3) δ 4.69 (d, J ) 5.5 Hz, 1H), 3.94 (m,
2H), 3.84-3.56 (m, 4H), 3.13-3.07 (m 1H), 2.75 (m, 1H), 2.45
(s, 3H), 1.25 (t, J ) 6.9 Hz, 6 H); 13C NMR (CDCl3) δ 103.85,
64.50, 63.00, 61.88, 55.74, 24.00, 15.24; mass spectrum (M)+
m/e 226; HRMS calcd for C8H18O3S2 (M + Na)+ m/e 249.0590,
measured 249.0591.
3,3-Dieth oxy-2-(m eth yld ith io)p r op en e (12). Into a dry
25 mL round-bottom flask under argon was combined the
bromide 9 (0.160 g, 0.553 mmol), tetrabutylammonium acetate
(0.276 g, 0.914 mmol), and 15 mL of anhydrous THF. The
mixture was refluxed for 45 min, cooled, poured into saturated
sodium bicarbonate (10 mL), and extracted twice with ether
(15 mL). The organic layer was washed twice with water (10
mL) and once with brine (10 mL), dried (MgSO4), and
concentrated to 0.115 g (100%) of the desired product 12, as a
colorless oil. An analytical sample was obtained by purification
on Florisil (3% EtOAc/97% hexane eluent): 1H NMR (CDCl3)
δ 5.69 (s 1H), 5.64 (s 1H), 5.07 (s 1H), 3.69-3.47 (m, 4H), 2.37
(s, 3H), 1.24 (t, J ) 6.9 Hz, 6 H); 13C NMR (CDCl3) δ 111.97,
100.62, 61.59, 21.62, 15.03; mass spectrum (M)+ m/e 208. Anal.
Calcd for C8H16O2S2: C, 46.12; H, 7.74. Found: C, 45.98; H,
7.74.
3,3-Dieth oxy-2-m er ca p top r op a n -1-ol (17). Into a dry 25
mL round-bottom flask under argon was combined acetate 13
(0.043 g, 0.160 mmol) and 8 mL of anhydrous ether. The
mixture was cooled to -10 °C in an ice/methanol bath and then
treated with lithium aluminum hydride (0.026 g, 0.685 mmol).
After being stirred at room temperature overnight, the mixture
was returned to -10 °C and quenched by the dropwise addition
of NaHSO4 (2 mL, saturated). The resultant mixture was
extracted twice with ether (15 mL). The organic layer was
washed twice with water (10 mL), dried (MgSO4), and con-
centrated to 0.027 g (94%) of the desired product 17, as a
colorless oil. An analytical sample (17) was obtained by
purification on Florisil (10% EtOAc/90% hexane eluent): 1H
NMR (CDCl3) δ 4.57 (d, J ) 5.1 Hz, 1H), 3.87-3.45 (m, 6H),
3.12-3.03 (m 1H), 2.75 (m, 1H), 1.74 (d, J ) 9.1 Hz, 1H), 1.25
(t, J ) 6.9 Hz, 6 H); 13C NMR (CDCl3) δ 105.82, 64.68, 64.21,
63.27, 43.86, 15.27, 15.18; mass spectrum for the disulfide (M
3,3-Dieth oxy-2-(m eth yld ith io)p r op a n -1-ol Aceta te (13).
Into a dry 25 mL round-bottom flask under argon was
(22) When the reaction volume was not allowed to decrease by
evaporation of the ether, the starting material was returned un-
changed.
(21) Pederson, R. L.; Liu, K. K. C.; Rutan, J . F.; Chen, L.; Wong,
C.-H. J . Org. Chem. 1990, 55, 4897-4901.

914 J . Org. Chem., Vol. 66, No. 3, 2001
Silvestri and Wong
+ Na)+ m/e 381; HRMS calcd for C14H30O6S2 (M + Na)+ m/e
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 9-14, 16, and 17 are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
381.1376, measured 381.1390.
Ack n ow led gm en t. Support from the National In-
stitutes of Health, GM44154, is gratefully acknowl-
edged.
J O001392V