Synthesis of 2-Substituted Polyhydroxytetrahydropyrimidines (N-Hydroxy Cyclic Guanidino-Sugars): Transition-State Mimics of Enzymatic Glycosidic Cleavage

Article abstract of DOI:10.1021/jo9915574

The synthesis of 2-substituted polyhydroxytetrahydropyrimidines as transition-state mimics of enzymatic glycosidic cleavage has been achieved by using guanylation and cyclization methodologies. The D-galacto type N-hydroxy cyclic guanidino-sugar 21 was synthesized in six steps from amine 7 and thiourea 14 in an overall yield of 59%. To further derivatize compound 21 to incorporate the leaving group moiety, we have synthesized 2-methylsulfanyl compounds 26-29 as key intermediates. The 2-methylsulfanyl group in 29 was displaced with amines, assisted by silver tetrafluoroborate as Lewis acid, to give protected cyclic guanidines 30-32 in moderate yields (60-67%). Removal of the protecting groups in 32 gave the D-galacto-type N-hydroxy cyclic guanidino-sugar 34. The key steps in the synthesis of the 6-deoxy-DL-galacto type N-hydroxy cyclic guanidino-sugars 49, 54, and 64-66 involve cyclization of the appropriate acetal intermediates (45, 50, and 58-60) followed by removal of the protecting groups.

Full text of DOI:10.1021/jo9915574

J . Org. Chem. 2000, 65, 2399-2409
2399
Syn th esis of 2-Su bstitu ted P olyh yd r oxytetr a h yd r op yr im id in es
(N-Hyd r oxy Cyclic Gu a n id in o-Su ga r s): Tr a n sition -Sta te Mim ics of
En zym a tic Glycosid ic Clea va ge
Van-Duc Le 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
Received October 6, 1999
The synthesis of 2-substituted polyhydroxytetrahydropyrimidines as transition-state mimics of
enzymatic glycosidic cleavage has been achieved by using guanylation and cyclization methodologies.
The D-galacto type N-hydroxy cyclic guanidino-sugar 21 was synthesized in six steps from amine
7 and thiourea 14 in an overall yield of 59%. To further derivatize compound 21 to incorporate the
leaving group moiety, we have synthesized 2-methylsulfanyl compounds 26-29 as key intermedi-
ates. The 2-methylsulfanyl group in 29 was displaced with amines, assisted by silver tetrafluo-
roborate as Lewis acid, to give protected cyclic guanidines 30-32 in moderate yields (60-67%).
Removal of the protecting groups in 32 gave the D-galacto-type N-hydroxy cyclic guanidino-sugar
34. The key steps in the synthesis of the 6-deoxy-DL-galacto type N-hydroxy cyclic guanidino-sugars
49, 54, and 64-66 involve cyclization of the appropriate acetal intermediates (45, 50, and 58-60)
followed by removal of the protecting groups.
In tr od u ction
type9 have been developed as glycosidase inhibitors, as
these compounds mimic the electronic character and
conformation of the transition state of enzymatic glyco-
side hydrolysis. These enzymatic reactions are thought
to proceed through a flattened half-chair (or twisted-boat)
transition state with substantial sp2 character at the
anomeric position10 (Figure 1). We and others11 have
shown that transition-state analogues that are neutral
at physiological pH and protonated upon binding are
effective inhibitors of glycosidases. Ichikawa and another
group12 have demonstrated that 1-N-iminosugars 1 (ni-
trogen atom at the anomeric position) are highly potent
and specific inhibitors of â-glycosidases, whereas DNJ -
type iminosugars 2 (nitrogen atom replacing the ring oxy-
gen) are potent inhibitors of R-glycosidases13 (Figure 2).
In an effort to develop new transition-state analogue
inhibitors of glycosidases, we have reported a study of
cyclic guanidino-sugars.11a We have demonstrated that
these inhibitors (4-6) are pH dependent and that the
Inhibitors of glycosidases are useful for the study of
the biological functions of oligosaccharides.1 They are also
potential as drugs for the treatment of a variety of car-
bohydrate-mediated diseases;2 for example, some glycosi-
dase inhibitors are finding clinical application as anti-
HIV,3 anticancer,4 antidiabetic,5 and antiviral agents.6
Development of new novel structures as glycosidase
inhibitors is thus of considerable interest to synthetic
chemists.7
Polyhydroxylated azaheterocycles having a resonance-
stabilized π-system of the amidine8 or cyclic guanidine
(1) (a) Albein, A. D. Annu. Rev. Biochem. 1987, 56, 497-534. (b)
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Res. 1995, 1, 935-944.
(5) (a) J oubert, P. H.; Venter, C. P.; J oubert, H. F.; Hillebran, I. Eur.
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Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res. 1993, 26, 182-
190. (f) Ganem, B. Acc. Chem. Res. 1996, 29, 340-347. (g) Gijsen, H.
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Chem., Int. Ed. Engl. 1995, 34, 412-432 and 521-546.
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S. W.; Colman, P. M.; Varghese, J . N.; Ryan, D. M.; Woods, J . M.;
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10.1021/jo9915574 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/28/2000

2400 J . Org. Chem., Vol. 65, No. 8, 2000
Le and Wong
cyclization proceeded smoothly to the undesired lactam
12 in moderate yield; however, none of the desired prod-
uct 13 was observed (Scheme 1). The structure of 12 was
confirmed by crystal structure analysis (Figure 3).
Syn th esis of th e D-Ga la cto-Typ e P yr im id in o Su g-
a r s 21, 34, a n d 40 (Sch em es 2-4). To avoid cyclization
through the nitrogen atom, which is attached to the
benzyl group, we have synthesized compound 16, a
carbamate derivative of 11. Guanylation of thiourea 1416
with amine 7 under standard conditions, followed by
removal of the TBDPS group in 15 with TBAF, gave the
alcohol 16. Dess-Martin oxidation17 of the alcohol 16 at
room temperature for 6 h gave the hemiaminal 17 as a
single isomer (J 4-5 ) 2.5 Hz). No lactam was observed.
The relative configuration of 17 was not readily deter-
F igu r e 1. Expected transition state (left) and its mimic (right)
in an R-galactosidase reaction. It is proposed that the neutral
form of the cyclic guanidino-sugar is accepted by the enzyme
followed by protonation from one of the two carboxyl groups
to form a tight charge complex.
1
mined from the H NMR coupling constants due to the
presence of flattened chair conformations. We therefore
determined the structure of 17 by X-ray structural
analysis (Figure 3). Protection of 17 with an acetyl or a
TES group gave compounds 18 and 19 in 82% and 79%
yield, respectively. An attempt to remove the CBz group
in 18 or 19 without affecting the benzyl group by
hydrogenolysis in a mixture of ethyl acetate/Et3N was
unsuccessful. The reaction was slow, and the starting
material was recovered in moderate yield. However,
when EtOAc or AcOH was used as the solvent, both of
the benzyl and CBz groups in 17 were removed to give
the acetonide 20 as a single isomer (J 4-5
2.4 Hz).
)
Attempts to derivatize 20 by alkylation were unsuccess-
ful; there was no reaction between benzyl bromide and
the guanidine 20 at room temperature or at reflux.18a,b
The isopropylidene group in 20 was removed with aque-
ous HCl in methanol to give the D-galacto-type pyrimi-
dino sugar 21 in 59% yield (Scheme 2).
F igu r e 2. General design strategy of glycosidase inhibitor.
neutral, tetrahydropyrimidine form is the most potent
form of the guanidino sugars (Chart 1). 2-Deoxy- and
3-deoxyguanidino-sugars have been reported;9b,11a how-
ever, these compounds may have an insufficient hydroxyl
topography for the targeting of specific glycosidases. A
proper transition-state analogue should mimic both the
steric and electrostatic properties of the transition state.
Here, we describe the synthesis of guanidino sugar 3 (X
) NH, see Figure 2) with an extra hydroxyl group on
the 3-N-position of the pyrimidyl ring. This extra hy-
droxyl group may play an important role in mimicking
both the steric and electrostatic properties of the transi-
tion-state. We also describe the synthesis of other 2-sub-
stituted pyrimidino sugars, notably the sulfur analogues
(3, X ) S).
Because of the difficulty of derivatizing the guanidine
20, we decided to seek a different method (Scheme 3).
The isothiocyanate 8 was converted into its thiourea 22,
followed by S-alkylation with iodomethane, to give com-
pound 23 in 97% yield. Removal of the TBDPS group in
23 with TBAF followed by oxidation of the alcohol 24 with
Dess-Martin reagent gave the cyclic hemiaminal 25. The
1H NMR spectrum of 25 shows small J 4,5 and J 5,6 values
(2.5-3.0 Hz), which is indicative of a gauche disposition
for the corresponding protons. The (4R)-5E configuration
1
of 25 (Figure 4) was supported by the H NMR spectrum
in CDCl3 that showed the H-4 signal as a doublet at δH
4.70 with a coupling constant of 2.5 Hz, similar to that
of cyclic hemiaminal 17 (δ 4.72, J 2.5 Hz).
Treatment of 25 with acetic anhydride in pyridine gave
the acetate 26 in 77% yield. Guanylation of 26 with
2-methoxyethylamine in the presence of silver tetrafluo-
roborate only gave a trace of the desired product. A
similar observation was obtained with the MOM deriva-
tive 27. Interestingly, starting with the triethylsilyl
derivative 29, guanylation with 2-methoxyethylamine
proceeded smoothly to give the protected guanidine 32
Resu lts a n d Discu ssion
F ir st Attem p t a t th e Syn th esis of Cyclic 3-N-
Hyd r oxygu a n id in o Su ga r (Sch em e 1). We began our
investigation on the regio- and stereoselectivity of the
cyclization reaction of compound 11. The isothiocyanate
8, which was made from the amine 7,14 was transformed
into thiourea 9 by heating it with benzylamine in toluene.
Guanylation of the thiourea 9 with O-benzylhydroxy-
lamine followed by desilylation of the guanidine 10 with
TBAF gave the alcohol 11 in 82% overall yield. Oxidation
of this alcohol 11 under Swern conditions gave a complex
mixture as visualized by TLC, and no identifiable prod-
ucts were isolated. Using Ley’s oxidation protocol,15 the
(15) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(16) J irgensons, A.; Kums, I.; Kauss, V.; Kalvins, I. Synth. Commun.
1997, 27, 315-322.
(17) Dess, D. B.; Martin. J . C. J . Org. Chem. 1983, 48, 4156.
(18) (a) Sta¨hle, H.; Daniel, H. J . Med. Chem. 1980, 23, 1217-1222.
(b) Augstein, J .; Green, S. M.; Monro, A. M.; Potter, G. W. H.; Worthing,
C. R.; Wrigley, T. I. J . Med. Chem. 1965, 8, 446. (c) Ritter, J .; Gleiter,
R.; Irngartinger, H.; Oeser, T. J . Am. Chem. Soc. 1997, 119, 10599-
10607. (d) Lehmann, J .; Rob, B.; Wagenknecht, H.-A. Carbohydr. Res.
1995, 278, 167-180.
(14) Compound 7 was prepared in five steps from 2-butene-1,4-diol;
see ref 11a.

Synthesis of 2-Substituted Polyhydroxytetrahydropyrimidines
J . Org. Chem., Vol. 65, No. 8, 2000 2401
Ch a r t 1. In h ibition of r- a n d â-Ga la ctosid a ses w ith Kn ow n Gu a n id in o-Su ga r s
a
b
See ref 9c. See ref 11a.
Sch em e 1a
alcohol 41 with TBDMS followed by reduction of the azide
42 gave amine 43. Without purification, 43 was subjected
to benzoyl isothiocyanate, from which thiourea 44 was
formed. Guanylation of 44 with O-benzylhydroxylamine
and mercuric chloride11a in DMF gave protected guani-
dine 45 in excellent yield (93%). Cyclization of 45 to cyclic
guanidine 46 was achieved with trifluoroacetic acid and
desilylation of compound 46 with TBAF gave diol 47. An
attempt to remove the benzyl group from 47 by hydro-
genolysis gave a complex mixture, and no identifiable
products were isolated. However, when the diol 47 was
converted to the acetate 48, the benzyl group was easily
be removed. Finally, the acetyl group was removed with
ammonia in methanol to give the 6-deoxy-DL-galacto-type
1
pyrimidino sugar 49 (Scheme 5). The H NMR spectrum
of 49 confirmed that the configuration was 4,5-trans. The
coupling constant J (4, 5) was small (2.5 Hz), indicating
a trans-diequatorial configuration.
The synthesis of 54 began with guanylation of thiourea
1416 with amine 43 to give the protected guanidine 50.
Cyclization of this compound with trifluoroacetic acid
gave the hemiaminal 51 in 78% yield. The regio- and
stereochemistry of 51 was confirmed by X-ray analysis
(Figure 3). Protection of the secondary alcohol in 51 with
the TES group followed by debenzylation gave the N-hy-
droxy compound 53 in 58% yield. Finally, both of the silyl
protecting groups in 53 were removed with aqueous HF
in acetonitrile to afford the 6-deoxy-DL-galacto-type py-
rimidino sugar 54 in 75% yield (Scheme 6).
a
Reagents and conditions: (a) 1,1′-thiocarbonyldiimidazole,
EtOAc, rt/12 h; (b) BnNH2, PhCH3, 90 °C/6 h; (c) BnONH2HCl,
HgCl2, TEA, DMF, rt/12 h; (d) TBAF, THF, rt/1 h; (e) TPAP, NMO,
CH2Cl2, rt/4 h.
in 65% yield. Similar yields of 30 and 31 were obtained
when benzylamine and ethanolamine were used as
nucleophiles. Debenzylation of 32 under standard condi-
tions gave the N-hydroxy compound 33. Finally, removal
of both TES and isopropylidene groups in 33 with
trifluoroacetic acid gave the D-galacto-type pyrimidino
sugar 34 in 71% yield (Scheme 3).
The synthesis of 2-substituted pyrimido sugar 40 began
with conversion of the azide 3511a to the amine, which
without purification was treated with benzoyl isothiocy-
anate to give thiourea 36. The benzoyl-protecting group
in 36 was removed with KOH in methanol and repro-
tected with the BOC group to give 38 in 77% yield.
Alkylation of thiourea 38 with iodomethane followed by
cyclization with trifluoroacetic acid gave the pyrimindo
sugar 40 in good yield (two steps, 79%, Scheme 4). A
gauche arrangement of the hydrogen atoms at C-4 and
The synthesis of 64-66 began with isothiocyanate 55,
which was prepared from the amine 43 in two steps
(Scheme 7). Compound 55 was heated to reflux with
ammonium hydroxide in ethanol to yield thiourea 56,
which was then protected with the BOC group to give
57 in 79% yield. Alkylation of thiourea 57 with iodo-
methane, 1-iodopropane, and benzyl bromide gave the
corresponding S-alkylated compounds 58-60. Treatment
of these compounds with trifluoroacetic acid for 12 h gave
the cyclized products 61-63 in moderate yield (54-76%).
Finally, removal of the TBDMS group from 61-63 using
aqueous HF in acetonitrile gave the 6-deoxy-DL-galacto-
type pyrimidino sugars 64-66 (52-62%) as water-soluble
solids. The stereochemical assignment of hemiaminals
64-66 was confirmed by comparing the NMR spectra of
other hemi-aminals (12, 17, and 51) that have been
5
C-5 with a coupling constant J 4,5 of 3.0 Hz proves the E
conformation in compound 40, with pseudoanomeric
4-OH in an axial disposition. This is in agreement with
Gleiter et al.,18c who have postulated that the axial
orientation of the nitrogen lone pair orbital increases the
axial preferences for the pseudoanomeric hydroxyl group
at C-4 in a six membered azaheterocycles.
1
determined by X-ray structural analysis. The H NMR
spectra of 64-66 showed small coupling constants (2.5-
3.0 Hz) between H4, H5, and H6, indicating that H4 and
H5 protons are equatorial and H6 is axial.
A preliminary biological evaluation was carried out on
Syn th esis of th e 6-Deoxy-DL-ga la cto-Typ e P yr i-
m id in o Su ga r s 49, 54, a n d 64-66 (Sch em e 5). The
synthesis of 49 began with the alcohol 41, which was
prepared by a known procedure.19 Protection of the
compounds 21, 34, 40, 49, 54, and 64-66. The com-
(19) Straub, A.; Effenberger, F.; Franz, P. J . Org. Chem. 1990, 55,
3926-3932.

2402 J . Org. Chem., Vol. 65, No. 8, 2000
Le and Wong
F igu r e 3. ORTEP diagram of compounds 12, 17, and 51.
Sch em e 2a
from bovine kidney (compound 40, IC50 500 µM; com-
pound 64, IC50 46 µM; compound 65, IC50 140 µM and
compound 66, IC50 230 µM). Even though these guanidino
sugars have sufficient hydroxyl topography for targeting
specific glycosidases and they have proper conformation
as transition-state analogue,18d it is unclear why they are
weak inhibitors. One possibility is that they are either
highly charged or lack an appropriate leaving group.
Work is in progress to further investigate this issue. The
chemistry described here is, however, useful for the
synthesis of this series of structures.
Exp er im en ta l Section
Gen er a l Meth od s. Tetrahydrofuran (THF), toluene, and
diethyl ether (Et2O) were distilled over sodium/benzophenone,
methylene chloride (CH2Cl2), and acetonitrile (CH3CN) over
calcium hydride. Reagentsof commercial quality were pur-
chased and used without further purification unless otherwise
stated. All reactions were carried out under an argon atmo-
sphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Reactions were monitored
by thin-layer chromatography carried out on 0.25 mm E.
Merck silica gel 60 F254 glass plates using UV light (254 nm)
as visualizing agent and a yellow solution containing Ce(NH4)2-
(NO3)6 (0.5 g) and (NH4)6Mo7O24‚4H2O (24.0 g) in 6% H2SO4
(500 mL) and heat as developing agent. Column chromatog-
raphy was performed on silica gel 60 Geduran (35-75 µm, EM
Science) or reversed-phase silica gel LiChroprep RP-18 (EM
Science). Inhibition studies were carried out on coffee bean
(CB) R-galactosidase, Aspergillus niger R-galactosidase, A.
niger â-galactosidase, and bovine kidney R-fucosidase. Libera-
a
Reagents and conditions: (a) 7, HgCl2, TEA, DMF, rt/24 h;
(b) TBAF, THF, rt/30 min; (c) Dess-Martin, CH2Cl2, rt/6 h; (d)
Ac2O, Py, rt/12 h or TESOTf, 2,6-lutidine, CH2Cl2, rt/1 h; (e) H2/
Pd-C, AcOH, H2O, rt/2 h; (f) 2.5 N HCl, MeOH, rt/24 h.
pounds were tested as inhibitors of R- and â-galactosi-
dases and R-fucosidase, but none of them exhibited any
significant activity. Compound 40 and compounds 64-
66 showed moderate activity against the R-fucosidase

Synthesis of 2-Substituted Polyhydroxytetrahydropyrimidines
J . Org. Chem., Vol. 65, No. 8, 2000 2403
Sch em e 3a
Sch em e 4a
a
Reagents and conditions: (a) H2/Pd-C, EtOH, rt/6 h,
PhCONCS, EtOAc, rt/12 h; (b) KOH, MeOH, rt/1 h; (c) BOC2O,
DMAP, Et3N, CH2Cl2, rt/2 h; (d) MeI, NaH, EtOH, rt/12 h; (e) TFA,
CH2Cl2, H2O, rt/12 h.
Sch em e 5a
a
Reagents and conditions: (a) BnONH2, PhCH3, 90 °C/6 h; (b)
MeI, NaH, EtOH, rt/30 min; (c) TBAF, THF, rt/30 min; (d) Dess-
Martin, CH2Cl2, rt/4 h; (e) Ac2O, Py, rt/12 h; MOMCl, NaH, THF,
rt/12 h; TBDMSOTf or TESOTf, 2,6-lutidine, CH2Cl2, rt/1 h; (f)
BnNH2 or 2-aminoethanol or 2-methoxethylamine, AgBF4, TEA,
CH3CN, rt/2 days; (g) H2/Pd-C, EtOAc, rt/2 h; (h) TFA, H2O,
CH2Cl2, rt/12 h.
F igu r e 4. Flattened-chair or envelope conformers for 2-sub-
stituted tetrahydropyrimidines.
tion of p-nitrophenolate was monitored at 400 nm on a
Beckman DU-6 spectrophotometer.
Com p ou n d 8. To a solution of 1,1′-thiocarbonyldiimidazole
(77 mg, 0.43 mmol) in EtOAc (2 mL) was added a solution of
amine 714 (172 mg, 0.43 mmol) in EtOAc (2 mL). The reaction
mixture was stirred at room temperature for 12 h. After
dilution with EtOAc (10 mL), the reaction mixture was washed
with water and brine, dried (MgSO4), concentrated, and
purified by flash chromatography on silica gel using hexanes/
EtOAc (9:1) as an eluent to give 8 (160 mg, 84%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 9H), 1.40 (s, 3H),
1.41 (s, 3H), 3.59 (q, J ) 1.8 Hz, 1H), 3.67-3.76 (m, 2H), 4.00
(dd, J ) 12.2 Hz, 1.7 Hz, 1H), 4.04 (m, 1H), 4.08 (dd, J ) 12.4
Hz, 1.8 Hz, 1H), 7.39-7.44 (m, 6H), 7.65-7.68 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 18.5, 19.2, 26.8, 28.9, 52.6, 62.8,
63.9, 71.1, 99.2, 127.8, 127.9, 129.8, 129.9, 132.6, 133.0, 135.5,
a
Reagents and conditions: (a) TBDMSOTf, 2,6-lutidine, CH2Cl2,
rt/1 h; (b) H2/Pd-C, EtOAc, rt/2 h; (c) PhCONCS, rt/4 h; (d)
BnONH2HCl, HgCl2, TEA, DMF, rt/24 h; (e) TFA, H2O, CH2Cl2,
rt/12 h; (f) TBAF, THF, rt/30 min; (g) Ac2O, Py, rt/12 h; (h) H2/
Pd-C, EtOH, rt/2 h; (i) NH3, MeOH, rt/6 h.
δ 1.03 (s, 9H), 1.26 (s, 3H), 1.33 (s, 3H), 3.45 (m, 1H), 3.59 (m,
1H), 3.82 (dd, J ) 12.0 Hz, 1.5 Hz, 1H), 3.90 (d, J ) 11.0 Hz,
1H), 4.42 (m, 2H), 7.18-7.24 (m, 4H), 7.34-7.43 (m, 7H), 7.65-
7.66 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 18.3, 19.0, 26.7,
47.8, 49.0, 60.3, 63.3, 64.3, 71.9, 99.2, 127.4, 127.5, 127.6, 128.7,
129.6, 133.1, 135.5, 135.6, 181.8; HRMS (FAB) calcd for
C
31H40N2O3SSiCs 681.1583, found 681.1558.
Com p ou n d 10. Mercuric chloride (241 mg, 0.89 mmol) was
135.6; HRMS calcd for
574.0830.
C24H31NO3SSiCs 574.0848, found
Com p ou n d 9. To a solution of benzylamine (79µL, 0.72
mmol) in EtOAc (1 mL) was added isothiocyanate 8 (154 mg,
0.36 mmol) in PhCH3 (1 mL). The reaction mixture was stirred
at 90 °C for 6 h. The reaction mixture was allowed to cool to
room temperature, washed with water and brine, dried
(MgSO4), concentrated, and purified by flash chromatography
on silica gel using hexanes/EtOAc (8:2) as an eluent to give 9
(157 mg, 82%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
added in one portion to a solution of thiourea 9 (442 mg, 0.81
mmol), triethylamine (560 µL, 3.19 mmol), and O-benzylhy-
droxylamine hydrochloride (227 mg, 1.43 mmol) in DMF (6
mL) at 0 °C. The color of the reaction mixture changed to dark
yellow, and the reaction was then warmed to room tempera-
ture. After 12 h, a combination of brine solution and EtOAc
were added to the reaction. The aqueous layer was extracted
with EtOAc. The combined organic layers were washed with

2404 J . Org. Chem., Vol. 65, No. 8, 2000
Le and Wong
Sch em e 6a
chromatography on silica gel using hexanes/EtOAc (2:8) as an
eluent to give 11 (86 mg, 82%) as a white solid: 1H NMR (500
MHz, CDCl3) δ 1.10 (s, 3H), 1.37 (s, 3H), 3.19 (dd, J ) 11.5,
9.5 Hz, 1H), 3.36 (dd, J ) 11.5, 5.0 Hz, 1H), 3.59 (dt, J ) 21.0,
12.5, 2.0 Hz, 2H), 3.96 (dq, J ) 15.0, 9.5, 5.0, 1.0 Hz, 1H), 4.01
(dd, J ) 12.0, 2.5 Hz, 1H), 4.05 (d, J ) 10.0 Hz, 1H), 4.26 (dd,
J ) 15.5, 5.5 Hz, 1H), 4.30 (dd, J ) 15.5, 6.5 Hz, 1H), 4.79 (d,
J ) 11.0 Hz, 1H), 4.82 (d, J ) 11.0 Hz, 1H), 5.59 (t, J ) 6.0
Hz, 1H), 7.25-7.27 (m, 3H), 7.32-7.40 (m, 7H); 13C NMR (100
MHz, CDCl3) δ 18.4, 29.2, 44.2, 45.5, 60.2, 65.3, 71.5, 75.6,
98.5, 126.6, 127.7, 127.8, 128.3, 128.6, 128.9, 137.6, 138.1,
156.1; HRMS (FAB) calcd for C22H30N3O4 400.2236, found
400.2247.
Com p ou n d 12. To a solution of the alcohol 11 (57 mg, 0.14
mmol) and NMO (25 mg, 0.21 mmol) in dry dichloromethane
(1 mL) was added TPAP (3 mg, 0.05 equiv.). The reaction
mixture was stirred at room temperature for 4 h. After dilution
with EtOAc (5 mL), water (5 mL) was added. The organic layer
was separated, washed with brine, dried (MgSO4), concen-
trated, and purified by flash chromatography on silica gel
using hexanes/EtOAc (1:1) as an eluent to give 12 (32 mg, 57%)
as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.41 (s, 3H),
1.49 (s, 3H), 3.31 (t, J ) 1.5 Hz, 1H), 3.78 (dd, J ) 13.0, 2.0
Hz, 1H), 4.07 (dd, J ) 13.0, 2.5 Hz, 1H), 4.50 (t, J ) 2.0 Hz,
1H), 4.92 (d, J ) 14.0 Hz, 1H), 4.94 (d, J ) 12.0 Hz, 1H), 4.97
(d, J ) 15.0 Hz, 1H), 4.98 (d, J ) 11.5 Hz, 1H), 5.22 (s, 1H),
7.21-7.23 (m, 4H), 7.26-7.34 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 19.1, 28.5, 43.8, 44.3, 61.1, 67.9, 76.0, 99.4, 127.2,
127.8, 128.1, 128.3, 128.5, 128.6, 137.0, 137.9, 147.8, 163.8;
HRMS (FAB) calcd for C22H26N3O4 396.2080, found 396.2090.
Com p ou n d 15. Mercuric chloride (176 mg, 0.65 mmol) was
added in one portion to a solution of thiourea 1416 (186 mg,
0.59 mmol), triethylamine (24 µL,1.76 mmol), and the crude
amine 7 (235 mg, 0.59 mmol) in DMF (14 mL) at 0 °C. The
color of the reaction mixture changed to dark yellow, and the
reaction was then warmed to room temperature. After 24 h, a
combination of brine solution and EtOAc was added to the
reaction. The aqueous layer was extracted with EtOAc. The
combined organic layers were wash with 1 M sodium bicar-
bonate solution, filtered through Celite, dried with MgSO4,
and concentrated in vacuo to afford a pale yellow foam. The
crude product was purified by flash chromatography on
silica gel using hexanes/EtOAc (1:1) as an eluent to give 15
(350 mg, 87%) as a colorless foam: 1H NMR (400 MHz,
CDCl3) δ 1.05 (s, 9H), 1.40 (s, 3H), 1.43 (s, 3H), 3.65 (dd, J )
10.1, 5.8 Hz, 1H), 3.73-3.80 (m, 2H), 3.91 (ABq, J ) 21.3, 11.8
Hz, 2H), 4.12 (t, J ) 5.9 Hz, 1H), 4.73 (d, J ) 11.4 Hz, 1H),
4.80 (d, J ) 11.4 Hz, 1H), 5.10 (ABq, J ) 15.0, 2.8 Hz, 1H),
6.93 (bs, 1H), 7.24-7.42 (m, 16H), 7.64-7.70 (m, 4H), 7.88 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 18.6, 19.1, 26.8, 29.4, 44.4,
63.2, 63.3, 67.5, 71.7, 75.7, 98.9, 127.5, 127.5, 127.6, 127.8,
128.2, 128.5, 128.6, 128.6, 129.5, 129.6, 133.4, 135.0, 135.4,
135.6, 135.7, 137.6, 147.6, 152.4; HRMS (FAB) calcd for
a
Reagents and conditions: (a) 43, HgCl2, TEA, DMF, rt/24 h;
(b) TFA, H2O, CH2Cl2, rt/24 h; (c) TESOTf, 2,6-lutidine, CH2Cl2,
rt/1 h; (d) H2/Pd-C, EtOAc, rt/2 h; (e) HF (49% in water), CH3CN,
rt/2 h.
Sch em e 7a
a
Reagents and conditions: (a) 1,1′-thiocarbonyldiimidazole,
EtOAc, rt/12 h; (b) NH4OH, EtOH, reflux/6 h; (c) BOC2O, DMAP,
TEA, CH2Cl2, rt/2 h; (d) MeI or PrI or BnBr, NaH, THF, rt/12 h;
(e) TFA, H2O, CH2Cl2, rt/12 h; (f) HF (49% in water), CH3CN,
rt/2 h.
C
39H47N3O6SiCs 814.2288, found 814.2256.
Com p ou n d 16. A solution of silyl ether 15 (420 mg, 0.61
an aqueous solution of NaHCO3, filtered through Celite, dried
with MgSO4, and concentrated in vacuo to afford a pale yel-
low oil. The crude product was purified by flash chromatog-
raphy on silica gel using hexanes/EtOAc (2:1) as an eluent to
give 10 (350 mg, 68%) as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 1.05 (s, 9H), 1.26 (s, 3H), 1.30 (s, 3H), 3.52 (dd, J )
8.0 Hz, 4.8 Hz, 1H), 3.59 (dd, J ) 8.0 Hz, 1.2 Hz, 1H), 3.67-
3.73 (m, 2H), 3.81 (dd, J ) 9.6 Hz, 1.2 Hz, 1H), 3.89 (dd, J )
9.2 Hz, 1.2 Hz, 1H), 4.00-4.02 (m, 1H), 4.05-4.10 (m, 1H),
4.75 (d, J ) 8.8 Hz, 1H), 4.82 (d, J ) 8.8 Hz, 1H), 5.41 (t, J )
4.8 Hz, 1H), 7.13-7.43 (m, 14H), 7.53-7.57 (m, 2H), 7.66-
7.69 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 18.4, 19.1, 26.8,
29.3, 44.5, 45.5, 63.5, 63.8, 72.3, 75.4, 98.8, 126.6, 127.5, 127.6,
127.8, 128.2, 128.5, 128.7, 129.5, 129.6, 129.8, 130.0, 133.6,
135.4, 135.5, 135.7, 138.7, 155.1; HRMS (FAB) calcd for
mmol) in dry THF (10 mL) was treated with n-Bu4NF (TBAF,
1.22 mL of a 1 M solution in THF, 1.22 mmol) and stirred at
25 °C for 30 min. After dilution with EtOAc (10 mL), water
(10 mL) was added. The organic layer was separated, washed
with brine, dried (MgSO4), concentrated, and purified by flash
chromatography on silica gel using hexanes/EtOAc (3:7) as an
eluent to give 16 (160 mg, 59%) as a colorless foam: 1H NMR
(500 MHz, CDCl3) δ 1.42 (s, 3H), 1.46 (s, 3H), 3.37 (dq, J )
21.0, 11.5, 9.5, 4.5 Hz, 1H), 3.47 (dt, J ) 22.0, 11.5, 5.5 Hz,
1H), 3.61 (dd, J ) 9.0, 1.5 Hz, 1H), 3.81 (dd, J ) 12.0, 1.5 Hz,
1H), 4.05 (dq, J ) 14.5, 9.0, 5.6 Hz, 1.0 Hz, 1H), 4.11 (d, J )
2.0 Hz, 1H), 4.13 (d, J ) 2.0 Hz, 1H), 4.58 (dd, J ) 10.5, 5.0
Hz, 1H), 4.80 (ABq, J ) 17.5, 11.0 Hz, 2H), 5.16 (ABq, J )
14.5, 12.0 Hz, 2H), 7.30-7.40 (m, 10H), 7.93 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 18.5, 29.5, 44.8, 60.7, 64.5, 67.9, 71.7, 75.9,
98.8, 128.1, 128.4, 128.6, 128.7, 128.7, 134.8, 136.9, 149.5,
152.6; HRMS (FAB) calcd for C23H30N3O6 444.2135, found
444.2120.
C
38H48N3O4Si 638.3414, found 638.3436.
Com p ou n d 11. A solution of silyl ether 10 (166 mg, 0.26
mmol) in dry THF (2 mL) was treated with n-Bu4NF (TBAF,
520 µL of a 1 M solution in THF, 0.52 mmol) and stirred at 25
°C for 1 h. After dilution with EtOAc (10 mL), water (5 mL)
was added. The organic layer was separated, washed with
brine, dried (MgSO4), concentrated, and purified by flash
Com p ou n d 17. To a solution of the alcohol 16 (160 mg, 0.36
mmol) in dry dichloromethane (3 mL) was added Dess-Martin

Synthesis of 2-Substituted Polyhydroxytetrahydropyrimidines
J . Org. Chem., Vol. 65, No. 8, 2000 2405
reagent (183 mg, 0.43 mmol). The reaction mixture was stirred
at room temperature for 6 h. After dilution with EtOAc (20
mL), water (10 mL) was added. The organic layer was
separated, washed with aqueous NaHCO3 and brine, dried
(MgSO4), concentrated, and purified by flash chromatography
on silica gel using hexanes/EtOAc (1:1) as an eluent to give
17 (120 mg, 75%) as a white solid: 1H NMR (500 MHz, CDCl3)
δ 1.35 (s, 3H), 1.40 (s, 3H), 2.72 (bs, 1H), 3.68 (d, J ) 13.0 Hz,
1H), 3.89 (dd, J ) 13.0, 2.0 Hz, 1H), 4.00 (t, J ) 2.5 Hz, 1H),
4.63 (d, J ) 10.0 Hz, 1H), 4.72 (d, J ) 2.5 Hz, 1H), 4.94 (d, J
) 10.0 Hz, 1H), 5.09 (d, J ) 13.0 Hz, 1H), 5.29 (d, J ) 13.0
Hz, 1H), 7.20-7.30 (m, 5H), 7.34-7.37 (m, 3H), 7.47-7.48 (m,
2H), 8.80 (bs, 1H).
Com p ou n d 18. A solution of compound 17 (20 mg, 0.05
mmol) in dry pyridine (0.5 mL) was treated with acetic
anhydride (0.5 mL) and stirred at room temperature for 12 h.
Evaporation of the reaction mixture, followed by purification
of the crude product using hexanes/EtOAc (6:4) as an eluent,
gave acetate 18 (18 mg, 82%) as a colorless oil: 1H NMR (500
MHz, CDCl3) δ 1.40 (s, 3H), 1.42 (s, 3H), 2.02 (s, 3H), 3.36 (m,
1H), 3.85 (dd, J ) 13.0, 2.0 Hz, 1H), 4.03 (t, J ) 2.5 Hz, 1H),
4.06 (dd, J ) 13.0, 2.0 Hz, 1H), 5.04 (ABq, J ) 25.5, 11.0 Hz,
2H), 5.18 (ABq, J ) 24.5, 12.5 Hz, 2H), 5.94 (d, J ) 3.5 Hz,
1H), 7.33-7.37 (m, 6H), 7.44-7.48 (m, 4H), 13C NMR (100
MHz, CDCl3) δ 18.4, 20.9, 29.0, 42.9, 61.7, 63.6, 66.9, 78.2,
80.5, 98.9, 127.6, 127.9, 128.3, 128.6, 130.1, 134.8, 137.2, 158.7,
164.5, 169.0; HRMS (FAB) calcd for C25H30N3O7 484.2084,
found 484.2069.
Com p ou n d 19. A solution of the alcohol 17 (100 mg, 0.23
mmol) and 2,6-lutidine (132 µL, 1.13 mmol) in dichloromethane
(3 mL) at 0 °C was treated with triethylsilyl trifluoromethane-
sulfonate (205 µL, 0.91 mmol). The reaction mixture was
allowed to warm to 25 °C and stirred for 1 h. After dilution
with EtOAc (10 mL), the reaction mixture was washed with
water and brine, dried (MgSO4), concentrated, and purified
by flash chromatography on silica gel using hexanes/EtOAc
(1:1) as an eluent to give 19 (100 mg, 79%) as a colorless
foam: 1H NMR (500 MHz, CDCl3) δ 0.58 (m, 6H), 0.87 (t, J )
8.0 Hz, 9H), 1.41 (s, 3H), 1.42 (s, 3H), 3.41 (d, J ) 2.0 Hz,
1H), 3.85 (dd, J ) 13.0, 1.5 Hz, 1H), 3.86 (d, J ) 3.5 Hz, 1H),
4.06 (dd, J ) 13.0, 2.0 Hz, 1H), 4.60 (d, J ) 3.5 Hz, 1H), 4.94
(d, J ) 11.5 Hz, 1H), 5.11 (d, J ) 11.0 Hz, 1H), 5.17 (ABq, J
) 20.0, 12.5 Hz, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 5H),
7.44-7.47 (m, 4H), 9.31 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
4.5, 6.6, 18.5, 29.1, 42.5, 62.2, 66.4, 66.7, 78.1, 81.6, 98.3, 127.5,
127.9, 128.2, 128.2, 128.4, 130.3, 135.2, 137.5, 158.5, 164.6;
EtOAc (8:2) as an eluent to give 22 (950 mg, 89%) as a color-
less oil: 1H NMR (500 MHz, CDCl3) δ 1.05 (s, 9H), 1.37 (s,
3H), 1.46 (s, 3H), 3.53 (dd, J ) 13.3, 7.8 Hz, 1H), 3.62 (dd,
J ) 13.4, 7.7 Hz, 1H), 3.86 (dd, J ) 15.1, 2.0 Hz, 1H), 4.04
(dd, J ) 15.1, 1.2 Hz, 1H), 4.16 (dt, J ) 7.7, 1.8 Hz, 1H), 4.54
(dd, J ) 11.4, 1.3 Hz, 1H), 4.68 (ABq, J ) 18.7, 14.0 Hz, 2H),
7.28-7.42 (m, 11H), 7.49 (d, J ) 11.6 Hz, 1H), 8.03 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 18.5, 19.1, 26.8, 29.5, 48.4, 63.4,
64.1, 71.9, 78.3, 99.3, 127.6, 127.7, 128.8, 129.1, 129.2, 129.7,
133.1, 133.2, 134.3, 135.7, 135.8, 181.7; HRMS (FAB) calcd
for C31H40N2O4SSiCs 697.1532, found 697.1554.
Com p ou n d 23. A solution of thiourea 22 (8.94 g, 15.9 mmol)
in ethanol (120 mL) was added dropwise to a stirred suspen-
sion of sodium hydride (0.64 g of a 95% dispersion in mineral
oil, 25.4 mmol) in ethanol (20 mL) at 25 °C. After 30 min,
iodomethane was added dropwise to the reaction mixture and
stirred for 1 h. Excess of solvent was removed in vacuo, and
the residue was dissolved in water (20 mL). The aqueous
solution was extracted with EtOAc, and the combined organic
extract was washed with brine, dried (MgSO4), and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography on silica gel using hexanes/EtOAc (8:2) as an eluent
gives 23 (8.90 g, 97%) as a colorless foam: 1H NMR (500 MHz,
CDCl3) δ 1.05 (s, 9H), 1.33 (s, 3H), 1.39 (s, 3H), 2.31 (s, 3H),
3.53-3.58 (m, 2H), 3.74 (m, 1H), 3.76 (d, J ) 10.0 Hz, 1H),
3.96 (d, J ) 12.0 Hz, 1H), 4.02 (m, 1H), 4.99 (s, 2H), 6.09 (d,
J ) 10.5 Hz, 1H), 7.23-7.30 (m, 4H), 7.33-7.37 (m, 5H), 7.38-
7.40 (m, 2H), 7.63-7.67 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 13.5, 18.5, 19.1, 26.8, 29.4, 4.0, 62.9, 65.2, 71.9, 75.4, 99.0,
127.4, 127.6, 128.0, 128.1, 129.6, 129.7, 133.2, 133.4, 135.6,
135.6, 138.3, 153.5; HRMS (FAB) calcd for C32H42N2O4SiCs
711.1689, found 711.1712.
Com p ou n d 24. A solution of silyl ether 23 (9.66 g, 16.7
mmol) in dry THF (140 mL) was treated with n-Bu4NF (TBAF,
33 mL of a 1 M solution in THF, 33.4 mmol) and stirred at 25
°C for 30 min. After dilution with EtOAc (100 mL), water (100
mL) was added. The organic layer was separated, washed with
brine, dried (MgSO4), concentrated, and purified by flash
chromatography on silica gel using hexanes/EtOAc (1:1) as an
eluent to give 24 (4.20 g, 74%) as a colorless foam: 1H NMR
(500 MHz, CDCl3) δ 1.41 (s, 3H), 1.47 (s, 3H), 2.33 (s, 3H),
3.42 (d, J ) 11.0 Hz, 1H), 3.45 (d, J ) 6.5 Hz, 2H), 3.71 (d, J
) 12.5 Hz, 1H), 4.03 (d, J ) 12.0 Hz, 1H), 4.07 (t, J ) 6.0 Hz,
1H), 5.01 (s, 2H), 6.13 (d, J ) 10.5 Hz, 1H), 7.26-7.39 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 13.4, 18.5, 29.4, 47.3, 62.4,
64.9, 72.0, 75.5, 99.2, 127.5, 128.1, 128.2, 138.1, 153.0; HRMS
(FAB) calcd for C16H25N2O4S 341.1535, found 341.1528.
Com p ou n d 25. To a solution of the alcohol 24 (445 mg, 1.31
mmol) in dry dichloromethane (10 mL) was added Dess-
Martin reagent (776 mg, 1.83 mmol). The reaction mixture was
stirred at room temperature for 4 h. After dilution with EtOAc
(20 mL), water (10 mL) was added. The organic layer was
separated, washed with aqueous NaHCO3 and brine, dried
(MgSO4), concentrated, and purified by flash chromatography
on silica gel using hexanes/EtOAc (1:1) as an eluent to give
25 (370 mg, 84%) as a colorless foam: 1H NMR (500 MHz,
CDCl3) δ 1.37 (s, 3H), 1.43 (s, 3H), 2.33 (s, 3H), 3.31 (q, J )
3.0 Hz, 1H), 4.05 (dd, J ) 11.5, 3.0 Hz, 1H), 4.14 (dd, J ) 11.5,
3.5 Hz, 1H), 4.17 (t, J ) 3.0 Hz, 1H), 4.70 (d, J ) 2.5 Hz, 1H),
4.89 (d, J ) 10.5 Hz, 1H), 4.97 (d, J ) 10.5 Hz, 1H), 7.36-
7.41 (m, 3H), 7.46-7.51 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 12.8, 19.3, 28.6, 48.7, 64.2, 68.4, 78.2, 81.8, 98.2, 128.5, 128.8,
HRMS (FAB) calcd for
688.1844.
C29H41N3O6SiCs 688.1819, found
Com p ou n d 20. A mixture of silyl ether 19 (94 mg, 0.17
mmol) and palladium on carbon (10%, 10 mg) in acetic acid/
water (9:1, 1 mL) was vigorously stirred under an atmosphere
of H2 at room temperature for 2 h, the reaction mixture was
filtered through a Celite pad, and the filter cake was washed
with methanol. The combined filtrates were concentrated to
give compound 20 (25 mg, 68%) as a white solid: 1H NMR
(400 MHz, CD3OD) δ 1.31 (s, 3H), 1.49 (s, 3H), 3.32 (m, 1H),
3.82 (dd, J ) 12.9, 1.6 Hz, 1H), 4.17 (m, 1H), 4.18 (dd, J )
12.9, 1.7 Hz, 1H), 4.76 (d, J ) 2.4 Hz, 1H); 13C NMR (125 MHz,
CD3OD) δ 18.8, 29.6, 43.4, 62.5, 67.8, 83.4, 99.8, 151.2; HRMS
(FAB) calcd for C8H16N3O4 218.1141, found 218.1138.
Com p ou n d 21. A solution of the acetonide 20 (25 mg, 0.12
mmol) in MeOH (1 mL) was treated with 2.5 N HCl (0.5 mL).
The reaction mixture was stirred at room temperature for 24
h. Removal of excess solvent to dryness affords compound
21 (12 mg, 59%) as a pale yellow solid: 1H NMR (500 MHz,
CD3OD) δ 3.60-3.63 (m, 1H), 3.72 (dd, J ) 10.5, 8.0 Hz, 1H),
3.79 (dd, J ) 11.0, 5.5 Hz, 1H), 3.90 (t, J ) 3.0 Hz, 1H), 4.92
(d, J ) 3.0 Hz, 1H); HRMS (FAB) calcd for C5H12N3O4
178.0828, found 178.0826.
129.6, 135.1, 157.1; HRMS (FAB) calcd for
339.2689, found 339.2612.
C16H23N2O4S
Com p ou n d 26. A solution of the alcohol 25 (2.30 g, 6.80
mmol) in dry pyridine (6 mL) was treated with acetic anhy-
dride (6 mL) and stirred at room temperature for 12h.
Evaporation of the reaction mixture to dryness followed by
purification of the crude product using hexanes/EtOAc (6:4)
as eluent gives acetate 26 (1.90 g, 77%) as a colorless foam:
1H NMR (400 MHz, CDCl3) δ 1.39 (s, 3H), 1.45 (s, 3H), 2.06
(s, 3H), 2.33 (s, 3H), 3.28 (ddd, J ) 6.0, 3.4, 2.6 Hz, 1H), 4.06
(dd, J ) 11.8, 2.6 Hz, 1H), 4.16 (dd, J ) 11.9, 3.6 Hz, 1H),
4.17 (t, J ) 3.2 Hz, 1H), 4.89 (s, 2H), 6.01 (d, J ) 3.2 Hz, 1H),
7.34-7.40 (m, 3H), 7.43-7.48 (m, 2H); 13C NMR (125 MHz,
Com p ou n d 22. A mixture of isothiocyanate 8 (839 mg, 1.90
mmol) and O-benzylhydroxylamine (234 mg, 1.90 mmol) in dry
toluene (6 mL) was stirred at 90 °C for 6 h. The reaction
mixture was allowed to cooled to room temperature, and the
solvent was removed in vacuo to dryness. The residue was
purified by flash chromatography on silica gel using hexanes/

2406 J . Org. Chem., Vol. 65, No. 8, 2000
Le and Wong
CDCl3) δ 12.8, 19.2, 21.1, 28.7, 48.6, 64.1, 66.7, 77.9, 79.7, 98.4,
128.4, 128.7, 129.9, 134.4, 156.1, 169.8; HRMS (FAB) calcd
for C18H25N2O5S 381.1484, found 381.1474.
1.48 (s, 3H), 1.50 (s, 3H), 3.65 (m, 1H), 4.08 (dd, J ) 13.3, 2.1
Hz, 1H), 4.14 (t, J ) 3.1 Hz, 1H), 4.22 (d, J ) 13.9 Hz, 1H),
4.22-4.23 (m, 1H), 4.37 (d, J ) 13.9 Hz, 1H), 4.78 (d, J ) 11.8
Hz, 1H), 4.81 (d, J ) 11.2 Hz, 1H), 4.99 (d, J ) 3.4 Hz, 1H),
7.26-7.45 (m, 10H); HRMS (FAB) calcd for C28H42N3O4Si
512.2945, found 512.2938.
Com p ou n d 27. A solution of the alcohol 25 (79 mg, 0.23
mmol) in dry THF (0.6 mL) was added dropwise to a stirred
suspension of sodium hydride (10 mg of an 95% dispersion in
mineral oil, 0.37 mmol) in THF (0.6 mL) at 25 °C. After 30
min, MOMCl (30µL, 0.37 mmol) was added dropwise to the
reaction mixture and the resulting mixture stirred for 12 h.
Excess solvent was removed in vacuo, and the residue was
dissolved in water (1 mL). The aqueous solution was extracted
with EtOAc, and the combined organic extract was washed
with brine, dried (MgSO4), and concentrated in vacuo. Puri-
fication of the residue by flash chromatography on silica gel
using hexanes/EtOAc (6:4) as eluent gives 27 (65 mg, 73%) as
a colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 3H), 1.46
(s, 3H), 2.32 (s, 3H), 3.20 (m, 1H), 3.56 (s, 3H), 4.06 (dd, J )
12.0, 2.5 Hz, 1H), 4.16 (dd, J ) 11.5, 3.5 Hz, 1H), 4.18 (m,
1H), 4.67 (d, J ) 6.5 Hz, 1H), 4.73 (d, J ) 3.0 Hz, 1H), 4.84 (d,
J ) 10.0 Hz, 1H), 4.90 (d, J ) 6.5 Hz, 1H), 4.94 (d, J ) 10.5
Hz, 1H), 7.34-7.38 (m, 3H), 7.45-7.46 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 12.7, 19.3, 28.7, 48.9, 55.8, 64.3, 68.0, 78.0,
84.6, 95.5, 98.1, 128.4, 128.6, 129.7, 134.9, 156.1; HRMS (FAB)
calcd for C18H27N5O3S 383.1641, found 383.1635.
Com p ou n d 28. A solution of the alcohol 25 (122 mg, 0.36
mmol) and 2,6-lutidine (84 µL, 0.72 mmol) in dichloromethane
(4 mL) at 0 °C was treated with tert-butyldimethylsilyl
trifluoromethanesulfonate (165 µL, 0.72 mmol). The reaction
mixture was allowed to warm to 25 °C and stirred for 1 h.
After dilution with EtOAc (10 mL), the reaction mixture was
washed with water and brine, dried (MgSO4), concentrated,
and purified by flash chromatography on silica gel using
hexanes/EtOAc (8:2) as an eluent to give 28 (120 mg, 74%) as
a colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.04 (s, 3H), 0.05
(s, 3H), 0.84 (s, 9H), 1.40 (s, 3H), 1.46 (s, 3H), 2.31 (s, 3H),
3.26 (q, J ) 6.0, 3.0 Hz, 1H), 4.05 (t, J ) 3.0 Hz, 1H), 4.07 (dd,
J ) 11.5, 2.5 Hz, 1H), 4.16 (dd, J ) 12.0, 3.5 Hz, 1H), 4.70 (d,
J ) 3.0 Hz, 1H), 4.82 (d, J ) 10.0 Hz, 1H), 4.94 (d, J ) 10.0
Hz, 1H), 7.34-7.37 (m, 3H), 7.45-7.47 (m, 2H); 13C NMR (100
MHz, CDCl3) δ -5.4, -4.6, 12.7, 17.9, 19.3, 25.6, 25.7, 28.8,
48.8, 64.5, 70.2, 77.9, 98.0, 128.3, 128.5, 129.7, 135.0, 153.2;
HRMS (FAB) calcd for C22H37N2O4SSi 453.2243, found 453.2253.
Com p ou n d 29. A solution of the alcohol 25 (227 mg, 0.67
mmol) and 2,6-lutidine (313 µL, 2.69 mmol) in dichloromethane
(4 mL) at 0 °C was treated with triethylsilyl trifluoromethane-
sulfonate (290 µL, 1.34 mmol). The reaction mixture was
allowed to warm to 25 °C and stirred for 1 h. After dilution
with EtOAc (10 mL), the reaction mixture was washed with
water and brine, dried (MgSO4), concentrated, and purified
by flash chromatography on silica gel using hexanes/EtOAc
(8:2) as an eluent to give 29 (260 mg, 86%) as a colorless
foam: 1H NMR (500 MHz, CDCl3) δ 0.52-0.63 (m, 6H), 0.88
(s, 9H), 1.40 (s, 3H), 1.45 (s, 3H), 2.31 (s, 3H), 3.33 (q, J ) 3.2,
2.7 Hz, 1H), 4.05 (t, J ) 3.3 Hz, 1H), 4.07 (dd, J ) 12.3, 2.4
Hz, 1H), 4.16 (dd, J ) 11.8, 3.6 Hz, 1H), 4.71 (d, J ) 3.1 Hz,
1H), 4.82 (d, J ) 10.3 Hz, 1H), 4.95 (d, J ) 10.3 Hz, 1H), 7.33-
7.37 (m, 3H), 7.45-7.47 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 4.6, 6.6, 12.7, 19.2, 28.8, 48.7, 64.5, 70.1, 78.0, 81.4, 97.9,
128.2, 128.4, 129.7, 135.0, 156.6; HRMS (FAB) calcd for
Com p ou n d 31. According to the general procedure, 29 (39
mg, 0.09 mmol), AgBF4 (34 mg, 0.17 mmol), triethylamine (36
µL, 0.26 mmol), and ethanolamine (30 µL, 0.43 mmol) gave
protected guanidine 31 (24 mg, 60%): 1H NMR (500 MHz,
CDCl3) δ 0.63 (q, J ) 7.9 Hz, 6H), 0.96 (t, J ) 7.9 Hz, 9H),
1.39 (s, 3H), 1.46 (s, 3H), 2.81 (ddd, J ) 26.0, 8.4, 2.6 Hz, 1H),
3.37 (d, J ) 1.8 Hz, 1H), 3.49 (dt, J ) 10.7, 2.3 Hz, 1H), 3.75
(dd, J ) 12.8, 1.5 Hz, 1H), 3.99 (dt, J ) 21.8, 10.9, 1.5 Hz,
1H), 4.08 (dd, J ) 12.8, 2.0 Hz, 1H), 4.12 (q, J ) 2.3 Hz, 1H),
4.21 (m, 1H), 4.49 (d, J ) 2.8 Hz, 1H), 4.82 (ABq, J ) 16.6,
5.2 Hz, 2H), 5.08 (bs, 1H), 5.45 (s, 1H), 7.27-7.30 (m, 1H),
7.32-7.35 (m, 2H), 7.39-7.41 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 4.1, 6.6, 18.7, 29.3, 42.0, 51.6, 60.1, 63.1, 64.7, 75.5,
81.3, 98.5, 127.5, 128.2, 128.4, 138.6, 151.2; HRMS (FAB) calcd
for C23H40N3O5Si 466.2737, found 466.2747.
Com p ou n d 32. According to the general procedure, 29 (70
mg, 0.15 mmol), AgBF4 (48 mg, 0.25 mmol), triethylamine (43
µL, 0.31 mmol), and 2-methoxethylamine (54 µL, 0.62 mmol)
gave protected guanidine 32 (48 mg, 65%): 1H NMR (500 MHz,
CDCl3) δ 0.64 (q, J ) 7.8 Hz, 6H), 0.93 (t, J ) 7.9 Hz, 9H),
1.47 (s, 3H), 1.49 (s, 3H), 3.28 (m, 1H), 3.34 (s, 3H), 3.41-3.48
(m, 2H), 3.54 (m, 2H), 4.07 (t, J ) 2.9 Hz, 1H), 4.10 (bs, 2H),
4.90 (d, J ) 3.4 Hz, 1H), 4.91 (d, J ) 11.4 Hz, 1H), 4.97 (d, J
) 11.5 Hz, 1H), 6.60 (bs, 1H), 7.40-7.45 (m, 3H), 7.47-7.49
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 4.4, 6.5, 18.5, 29.0, 41.6,
43.4, 58.8, 61.0, 67.0, 70.6, 78.6, 80.5, 98.9, 128.9, 129.9, 130.8,
132.8, 154.0; HRMS (FAB) calcd for C24H42N3O5Si 480.2894,
found 480.2812.
Com p ou n d 33. A mixture of protected guanidine 32 (27
mg, 0.06 mmol) and palladium on carbon (10%, 4 mg) in EtOAc
(2 mL) was vigorously stirred under an atmosphere of H2 at
room temperature for 2 h, the reaction mixture was filtered
through a Celite pad, and the filter cake was washed with
EtOAc. The combined filtrates were concentrated to give
compound 33 (17 mg, 85%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 0.67-0.72 (m, 6H), 0.96 (t, J ) 7.8 Hz, 9H),
1.39 (s, 3H), 1.48 (s, 3H), 3.43 (s, 3H), 3.45-3.47 (m, 1H), 3.50-
3.55 (m, 1H), 3.59-3.66 (m, 2H), 3.70-3.73 (m, 1H), 3.94 (dd,
J ) 13.0, 1.5 Hz, 1H), 4.02 (q, J ) 2.0 Hz, 1H), 4.17 (dd, J )
13.0, 1.5 Hz, 1H), 4.92 (d, J ) 2.5 Hz, 1H), 7.22 (t, J ) 6.0 Hz,
1H), 7.63 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ 4.4, 6.5, 18.2,
28.9, 42.7, 42.9, 59.2, 61.2, 67.3, 72.7, 82.6, 99.3, 154.5; HRMS
(FAB) calcd for C17H36N3O5Si 355.2650, found 355.2676.
Com p ou n d 34. Trifluoroacetic acid (0.5 mL) and water
(100µL) were added to a solution of N-hydroxy compound 33
(17 mg, 0.05 mmol) in dichloromethane (0.5 mL). The reaction
mixture was stirred at room temperature for 12 h, and excess
solvent was removed in vacuo. The residue was purified by
passing through a C-18 column using water as an eluent to
give 34 (8 mg, 71%) as a white solid: 1H NMR (400 MHz, D2O)
δ 3.38 (s, 3H), 3.48 (d, J ) 4.0 Hz, 1H), 3.49 (d, J ) 4.3 Hz,
1H), 3.62 (t, J ) 4.8 Hz, 2H), 3.66-3.70 (m, 1H), 3.75-3.86
(m, 2H), 4.08 (t, J ) 2.7 Hz, 1H), 5.05 (d, J ) 3.0 Hz, 1H); 13
C
C
22H37N2O4SSi 453.2243, found 453.2253.
NMR (125 MHz, D2O) δ 43.8, 53.1, 60.8, 61.9, 67.6, 73.5, 86.0,
156.0; HRMS (FAB), calcd for C8H18N3O5 236.1246, found
236.1240.
Gen er a l P r oced u r e for th e Syn th esis of P r otected
Gu a n id in es 30-32. To a mixture of silyl ether 29 (0.05-0.05
mmol), AgBF4 (1.6 equiv), and triethylamine (2 equiv) in dry
acetonitrile (1 mL) was added amine (3.8 equiv). The reaction
mixture was stirred at room temperature for 2 days. After
dilution with EtOAc (2 mL), the reaction mixture was filtered
through a pad of Celite. The filtrate was washed with water
and brine, dried (MgSO4), concentrated, and purified by flash
chromatography on silica gel using hexanes/EtOAc (1:9) as an
eluent to give protected guanidine as a colorless oil.
Com p ou n d 30. According to the general procedure, 29 (21
mg, 0.05 mmol), AgBF4 (15 mg, 0.08 mmol), triethylamine
(13µL, 0.10 mmol), and benzylamine (21 µL, 0.19 mmol) gave
protected guanidine 30 (16 mg, 67%): 1H NMR (500 MHz,
CDCl3) δ 0.66 (q, J ) 7.9 Hz, 6H), 0.96 (t, J ) 7.9 Hz, 9H),
Com p ou n d 36. A mixture of azide 3511a (200 mg, 0.77
mmol) and palladium on carbon (10%, 93 mg) in EtOH (6 mL)
was vigorously stirred under an atmosphere of H2 at room
temperature for 6 h, the reaction mixture was filtered through
a Celite pad, and the filter cake was washed with EtOH. The
combined filtrates were concentrated to give crude amine. This
was employed for the next step without further purification.To
a solution of the above amine in EtOAc (4 mL) was added
benzoyl isothiocyanate (0.10 mL, 0.77 mmol). The reaction
mixture was stirred at room temperature for 4 h. The reaction
mixture was washed with water and brine, dried (MgSO4),
concentrated, and purified by flash chromatography on silica
gel using hexanes/EtOAc (9:1) as eluent to give 36 (0.22 g, 72%)

Synthesis of 2-Substituted Polyhydroxytetrahydropyrimidines
J . Org. Chem., Vol. 65, No. 8, 2000 2407
as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J ) 7.0
Hz, 3H), 1.22 (t, J ) 7.0 Hz, 3H), 1.52 (s, 3H), 1.54 (s, 3H),
3.49-3.56 (m, 1H), 3.61-3.71 (m, 2H), 3.73-3.78 (m, 1H),
4.06-4.10 (m, 3H), 4.42 (d, J ) 7.2 Hz, 1H), 4.64 (dq, J ) 8.7,
5.0 Hz, 1.6 Hz, 1H), 7.50-7.54 (m, 2H), 7.60-7.64 (m, 1H),
7.86-7.88 (m, 2H), 9.04 (s, 1H), 9.74 (d, J ) 8.6 Hz, 1H);13C
NMR (125 MHz, CDCl3) δ 15.0, 15.4, 29.5, 50.4, 62.0, 63.4,
64.0, 71.4, 99.5, 100.8, 127.4, 129.0, 131.8, 133.4, 166.5, 179.1;
HRMS (FAB), calcd for C19H29N2O5S 397.1797, found 397.1801.
Com p ou n d 37. To a solution of thiourea 36 (0.2 g, 0.51
mmol) in methanol (6 mL) was added K2CO3 (70 mg). The
reaction mixture was stirred at room temperature for 30 min.
After dilution with ethyl acetate, the mixture was washed with
water and brine, dried (MgSO4), and concentrated in vacuo.
Purification of the residue by flash chromatography on silica
gel using hexanes/EtOAc (1:1) as an eluent gives 37 (98 mg,
66%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.20 (t, J
) 7.0 Hz, 6H), 1.50 (s, 3H), 1.56 (s, 3H), 3.44 (m, 1H), 3.56-
3.94 (m, 4H), 4.06-4.10 (m, 2H), 4.43 (d, J ) 6.4 Hz, 1H), 4.61
(m, 1H), 6.34 (s, 2H), 6.48 (s, 1H); 13C NMR (125 MHz, CDCl3)
δ 15.0, 15.4, 29.2, 49.6, 60.4, 62.1, 64.4, 64.8, 71.0, 72.4, 100.1,
183.2; HRMS (FAB) calcd for C12H25N2O4S 293.1535, found
293.15321.
Com p ou n d 38. To a mixture of thiourea 37 (50 mg, 0.17
mmol), DMAP (21 mg, 0.17 mmol), and Et3N (0.095 mL, 0.68
mmol) in CH2Cl2 (2 mL) was added a solution of BOC2O (45
mg, 0.21 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was
stirred at room temperature for 1 h. After dilution with EtOAc
(5 mL), the reaction mixture was washed with water and brine,
dried (MgSO4), concentrated, and purified by flash chroma-
tography on silica gel using hexanes/EtOAc (8:2) as eluent to
give 38 (52 mg, 77%) as a white solid: 1H NMR (400 MHz,
CDCl3) δ 1.20 (t, J ) 6.5 Hz, 3H), 1.21 (t, J ) 7.0 Hz, 3H),
1.49 (s, 3H), 1.50 (s, 9H), 1.55 (s, 3H), 3.48-3.77 (m, 4H), 3.95-
4.08 (m, 3H), 4.39 (dd, J ) 7.3, 1.6 Hz, 1H), 4.61 (dt, J ) 8.6,
3.2, 1.6 Hz, 1H), 8.03 (s, 1H), 10.40 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 15.0, 15.3, 18.3, 27.5, 27.9, 29.4, 49.9, 60.7,
63.6, 64.0, 70.9, 99.4, 100.3, 151.3, 178.9; HRMS (FAB) calcd
for C17H32N2O6SNa 415.1879, found 415.1867.
Com p ou n d 39. A solution of BOC derivative 38 (33 mg,
0.08 mmol) in dry THF (1 mL) was added dropwise to a stirred
suspension of sodium hydride (5 mg of an 95% dispersion in
mineral oil, 0.17 mmol) in THF (1 mL) at 25 °C. After 10 min,
iodomethane (10 µL, 0.16 mmol) was added dropwise to the
reaction mixture and stirred for 6 h. Excess of solvent was
removed in vacuo, and the residue was dissolved in water (1
mL). The aqueous solution was extracted with EtOAc, and the
organic extract was washed with brine, dried (MgSO4), and
concentrated in vacuo. Purification of the residue by flash
chromatography on silica gel using hexanes/EtOAc (6:4) as
eluent affords 39 (24 mg, 70%) as a colorless oil: 1H NMR (500
MHz, CDCl3) δ 1.18 (t, J ) 7.0 Hz, 3H), 1.20 (t, J ) 7.0 Hz,
3H), 1.47 (s, 3H), 1.49 (s, 3H), 1.52 (s, 9H), 2.47 (s, 3H), 3.44-
3.47 (m, 1H), 3.56-3.62 (m, 1H), 3.65-3.70 (m, 1H), 3.72-
3.78 (m, 2H), 3.82-3.84 (m, 1H), 3.97-4.03 (m, 2H), 4.38 (d,
J ) 7.0 Hz, 1H); HRMS (FAB) calcd for MH+ C18H35N2O6S
407.2216, found 407.2204.
Com p ou n d 40. Trifluoroacetic acid (1 mL) and water (100
µL) were added to a solution of 39 (24 mg, 0.06 mmol) in
dichloromethane (1 mL). The reaction mixture was stirred at
room temperature for 12 h, and excess solvents were removed
in vacuo to give 40 (10 mg, 88%) as a white solid: 1H NMR
(500 MHz, D2O) δ 2.49 (s, 3H), 3.66 (dt, J ) 13.5, 6.5, 2.5 Hz,
1H), 3.71 (dd, J ) 11.0, 7.0 Hz, 1H), 3.77 (dd, J ) 11.5, 6.5
Hz, 1H), 3.99 (t, J ) 3.0 Hz, 1H), 4.86 (d, J ) 3.0 Hz, 1H);
13C NMR (125 MHz, D2O) δ 15.2, 55.0, 61.4, 64.6, 77.3, 167.9;
HRMS (FAB) calcd for C6H13N2O3S 193.0647, found 193.0645.
Com p ou n d 42. A solution of alcohol 4119 (3.09 g, 15.2 mmol)
and 2,6-lutidine (3.90 mL, 33.5 mmol) in dichloromethane (60
mL) at 0 °C was treated with tert-butyldimethylsilyl trifluo-
romethanesulfonate (3.85 mL, 16.8 mmol). The reaction mix-
ture was allowed to warm to 25 °C and stirred for 1 h. After
dilution with ether (80 mL), the reaction mixture was washed
with water and brine, dried (MgSO4), concentrated, and
purified by flash chromatography on silica gel using hexanes/
EtOAc (95:5) as eluent to give 42 (4.10 g, 85%) as a colorless
oil: 1H NMR (500 MHz, CDCl3) δ 0.09 (s, 3H), 0.12 (s, 3H),
0.93 (s, 9H), 1.21 (t, J ) 7.06 Hz, 3H), 1.24 (t, J ) 7.05 Hz,
3H), 1.35 (d, J ) 6.92 Hz, 3H), 3.44 (dq, J ) 6.89, 2.07 Hz,
1H), 3.51 (dd, J ) 6.76, 2.13 Hz, 1H), 3.78-3.54 (m, 4H), 4.43
(d, J ) 6.70 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -4.7, -3.9,
15.1, 15.4, 16.0, 18.3, 25.9, 56.8, 64.7, 77.3, 104.3; HRMS (FAB)
calcd for C14H31N2O3SiNa 340.2032, found 340.2025.
Com p ou n d 44. A mixture of azide 42 (280 mg, 0.87 mmol)
and palladium on carbon (10%, 93 mg) in EtOAc (6 mL) was
vigorously stirred under an atmosphere of H2 at room tem-
perature for 2 h, the reaction mixture was filtered through a
Celite pad, and the filter cake was washed with EtOAc. The
combined filtrates were concentrated to give crude amine 43.
This was employed for the next step without further purifi-
cation.To a solution of the above amine 43 in EtOAc (4 mL)
was added benzoyl isothiocyanate (0.12 mL, 0.87 mmol). After
4 h at room temperature, the reaction mixture was washed
with water and brine, dried (MgSO4), concentrated, and
purified by flash chromatography on silica gel using hexanes/
EtOAc (9:1) as eluent to give 44 (0.25 g, 63%) as a colorless
oil: 1H NMR (500 MHz, CDCl3) δ 0.02 (s, 3H), 0.09 (s, 3H),
0.9 (s, 9H), 1.24 (t, J ) 7.05 Hz, 3H), 1.25 (t, J ) 7.0 Hz, 3H),
1.33 (d, J ) 6.76 Hz, 3H), 3.53 (m, 1H), 3.65 (m, 1H), 3.74 (m,
1H), 3.83 (m, 1H), 4.23 (dd, J ) 6.61, 2.32 Hz, 1H), 4.36 (d, J
) 6.62 Hz, 1H), 4.69 (m, 1H), 7.51 (t, J ) 7.66 Hz, 2H), 7.62
(t, J ) 7.52 Hz, 1H), 7.83 (d, J ) 7.33 Hz, 2H), 8.90 (bs, 1H),
10.62 (bd, 1H); 13C NMR (100 MHz, CDCl3) δ -5.0, -4.1, 13.5,
15.1, 18.2, 25.9, 53.8, 60.5, 63.3, 72.1, 102.8, 127.1, 129.1, 132.1,
133.7, 166.3, 178.4; HRMS (FAB) calcd for C22H38N2O4SSiCs
587.1376, found 587.1362.
Com p ou n d 45. Mercuric chloride (208 mg, 0.76 mmol) was
added in one portion to a solution of thiourea 44 (290 mg, 0.64
mmol), triethylamine (450µL, 3.19 mmol), and O-benzylhy-
droxylamine hydrochloride (204 mg, 1.28 mmol) in DMF (6
mL) at 0 °C. After 24 h at room temperature, a combination
of brine solution and EtOAc was added to the reaction mix-
ture. The aqueous layer was extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with 1 M
sodium bicarbonate solution, filtered through Celite, dried with
MgSO4, and concentrated in vacuo to afford a pale yellow oil.
The crude product was purified by flash chromatography on
silica gel using hexanes/EtOAc (2:1) as an eluent to give 45
(324 mg, 93%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 0.01 (3H, s), 0.02 (s, 3H), 0.85 (s, 9H), 1.10 (d, J ) 7.0 Hz,
3H), 1.11 (t, J ) 6.8 Hz, 6H), 3.41-3.62 (m, 4H), 3.47 (dd, J )
7.3 Hz, 1.6 Hz, 1H), 3.88 (m, 1H), 4.24 (d, J ) 7.2 Hz, 1H),
4.81 (ABq, J ) 22.0 Hz, 11.8 Hz, 2H), 7.16-7.31 (m, 8H),
7.38-7.46 (m, 1H), 7.58-7.60 (m, 2H), 9.04 (bs, 1H); 13C NMR
(125 MHz, CDCl3) δ -4.8, -4.0, 15.1, 15.3, 16.9, 18.2, 25.9,
46.9, 63.9, 64.4, 75.6, 75.7, 104.2, 127.1, 127.8, 128.2, 128.7,
132.4, 133.5, 137.9, 149.2, 165.3; HRMS (FAB) calcd for
C
29H45N3O5SiCs 676.2183, found 676.2197.
Com p ou n d 46. Trifluoroacetic acid (1 mL) and water (100
µL) were added to a solution of compound 45 (300 mg, 0.55
mmol) in dichloromethane (1 mL). The reaction mixture was
stirred at room temperature for 12 h, and the solvent was
removed in vacuo to give 46 (200 mg, 77%) as a pale yellow
solid: 1H NMR (500 MHz, CDCl3) δ 0.01 (s, 3H), 0.02 (s, 3H),
0.84 (s, 9H), 1.14 (d, J ) 6.7 Hz, 3H), 3.45 (m, 1H), 3.58 (bs,
1H), 4.84 (bs, 1H), 4.90 (d, J ) 10.2 Hz, 1H), 5.33 (d, J ) 10.2
Hz, 1H), 7.36-7.48 (m, 8H), 8.25 (d, J ) 7.2 Hz, 2H), 10.3 (bs,
1H); 13C NMR (100 MHz, CDCl3) δ -5.1, -4.5, 15.9, 17.9, 25.6,
45.0, 68.2, 77.9, 83.0, 127.7, 128.6, 128.7, 129.1, 129.4, 131.1,
135.3, 138.5, 157.9, 178.2; HRMS (FAB) calcd for C25H36N3O4-
Si 470.2475, found 470.2491.
Com p ou n d 47. A solution of silyl ether 46 (100 mg, 0.21
mmol) in dry THF (2 mL) was treated with n-Bu4NF (TBAF,
426 µL of a 1 M solution in THF, 0.43 mmol) and stirred at 25
°C for 30 min. After dilution with EtOAc (10 mL), water (5
mL) was added. The organic layer was separated, washed with
brine, dried (MgSO4), concentrated, and purified by flash
chromatography on silica gel using hexanes/EtOAc (2:8) as an
eluent to give 47 (62 mg, 82%) as a white solid: 1H NMR (500
MHz, CD3OD) δ 1.35 (d, J ) 6.8 Hz, 3H), 3.68 (m, 1H), 3.81-

2408 J . Org. Chem., Vol. 65, No. 8, 2000
Le and Wong
3.85 (m, 1H), 5.10 (d, J ) 10.0 Hz, 1H), 5.12 (m, 1H), 5.30 (d,
J ) 10.0 Hz, 1H), 7.35-7.41 (m, 5H), 7.45-7.48 (m, 1H),
7.56-7.57 (m, 2H), 8.15-8.17 (m, 2H); 13C NMR (100 MHz,
CD3OD) δ 15.8, 46.1, 69.2, 79.2, 84.5, 128.9, 129.5, 129.7, 130.1,
130.5, 132.4, 136.7, 139.8, 159.0, 179.4; HRMS (FAB) calcd
for C19H22N3O4 356.3998, found 356.3988.
Com p ou n d 48. A solution of the compound 47 (50 mg, 0.14
mmol) in dry pyridine (1 mL) was treated with acetic anhy-
dride (1 mL) and stirred at room temperature for 12 h.
Evaporation of the reaction mixture, followed by purification
of the crude product using hexanes/EtOAc (1:1) as eluent gave
acetate 48 (51 mg, 82%) as a colorless foam: 1H NMR (500
MHz, CDCl3) δ 1.26 (d, J ) 6.7 Hz, 3H), 2.06 (s, 3H), 2.08 (s,
3H), 3.95 (dq, J ) 7.0, 2.0 Hz, 1H), 4.90 (m, 1H), 5.18 (d, J )
10.0 Hz, 1H), 5.25 (d, J ) 10.0 Hz, 1H), 6.18 (d, J ) 2.5 Hz,
1H), 7.39-7.51(m, 8H), 8.27 (m, 2H), 10.71 (bs, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.5, 20.7, 20.9, 47.5, 61.9, 64.0, 78.4,
127.9, 128.2, 128.5, 128.9, 129.3, 129.7, 131.7, 134.7, 137.8,
158.0, 168.6, 169.1, 170.4, 179.0; HRMS (FAB) calcd for
Com p ou n d 52. A solution of the alcohol 51 (500 mg, 1.0
mmol) and 2,6-lutidine (580 µL, 5.0 mmol) in dichloromethane
(20 mL) at 0 °C was treated with triethylsilyl trifluoromethane-
sulfonate (1.13 mL, 5.0 mmol). The reaction mixture was
allowed to warm to 25 °C and stirred for 1 h. After dilution
with EtOAc (20 mL), the reaction mixture was washed with
water and brine, dried (MgSO4), concentrated, and purified
by flash chromatography on silica gel using hexanes/EtOAc
(6:4) as an eluent to give 52 (490 mg, 80%) as a colorless
foam: 1H NMR (400 MHz, CDCl3) δ 0.09 (s, 3H), 0.10 (s, 3H),
0.53-0.63 (m, 6H), 0.90 (t, J ) 7.8 Hz, 9H), 0.92 (s, 9H), 1.22
(d, J ) 6.8 Hz, 3H), 3.54 (dd, J ) 5.2, 2.2 Hz, 1H), 3.80 (dq, J
) 6.7, 2.1 Hz, 1H), 4.76 (d, J ) 9.9 Hz, 1H), 4.95 (d, J ) 3.2
Hz, 1H), 5.17 (d, J ) 2.4 Hz, 1H), 5.26 (d, J ) 9.9 Hz, 1H),
7.27-7.37 (m, 6H), 7.43-7.49 (m, 4H), 8.95 (bs, 1H); 13C NMR
(125 MHz, CDCl3) δ -5.0, -4.3, 4.6, 6.6, 16.2, 18.0, 25.7, 44.9,
66.6, 69.9, 77.8, 83.0, 127.4, 127.7, 128.2, 128.2, 128.3, 128.3,
129.3, 135.2, 137.6, 157.5, 164.5; HRMS (FAB) calcd for
C
32H52N3O5Si2 614.3446, found 614.3422.
C
23H26N3O6 440.2324, found 440.2360.
Com p ou n d 53. A mixture of the compound 52 (206 mg,
Com p ou n d 49. A mixture of diacetate 48 (51 mg, 0.12
0.34 mmol) and palladium on carbon (10%, 20 mg) in EtOAc
(4 mL) was vigorously stirred under an atmosphere of H2 at
room temperature for 2 h, the reaction mixture was filtered
through a Celite pad, and the filter cake was washed with
EtOAc. The combined filtrates were concentrated to give
compound 53 (77 mg, 58%) as a colorless foam: 1H NMR (400
MHz, CDCl3) δ 0.10 (s, 3H), 0.13 (s, 3H), 0.74 (m, 6H), 0.90
(m, 9H), 0.98 (m, 9H), 1.23 (d, J ) 6.8 Hz, 3H), 3.51 (bs, 1H),
3.62-3.64 (m, 1H), 4.80 (d, J ) 2.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ -4.9, -4.3, 7.2, 7.4, 16.0, 19.0, 26.3, 45.8, 71.6,
85.6, 151.1; HRMS (FAB) calcd for C17H40N3O3Si2 390.2608,
found 390.2602.
Com p ou n d 54. To a solution of the compound 53 (77 mg,
0.20 mmol) in acetonitrile (2 mL) was added aqueous HF (50%
in water, 0.2 mL). The reaction mixture was stirred for 2 h,
and the solvent was removed in vacuo to give 54 (24 mg, 75%)
as a pale yellow solid: 1H NMR (500 MHz, D2O) δ 1.32 (d, J
) 6.8 Hz, 3H), 3.65 (t, J ) 2.6 Hz, 1H), 3.86 (dq, J ) 7.0, 2.5
Hz, 1H), 4.76 (d, J ) 2.5 Hz, 1H); HRMS (FAB) calcd for
C5H11N3O3 162.0879, found 162.0874.
Com p ou n d 55. To a solution of 1,1′-thiocarbonyldiimidazole
(1.28 g, 7.19 mmol) in EtOAc (20 mL) was added a solution of
the crude amine 43 (2.09 g, 7.19 mmol) in EtOAc (5 mL). The
reaction mixture was stirred at room temperature for 12 h.
After dilution with EtOAc (10 mL), the reaction mixture was
washed with water and brine, dried (MgSO4), concentrated,
and purified by flash chromatography on silica gel using
hexanes/EtOAc (8:2) as eluent to give 55 (1.20 g, 50%) as a
pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.08 (s, 3H), 0.11
(s, 3H), 0.93 (s, 9H), 1.22 (t, J ) 7.0 Hz, 3H), 1.23 (t, J ) 7.0
Hz, 3H), 1.36 (d, J ) 6.5 Hz, 3H), 3.47 (dd, J ) 6.5, 2.0 Hz,
1H), 3.54-3.59 (m, 1H), 3.63-3.67 (m, 1H), 3.70-3.77 (m,
2H), 3.92 (dq, J ) 13.5, 6.5, 2.0 Hz, 1H), 4.35 (d, J ) 6.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ -4.8, -3.9, 15.1, 15.4,
19.3, 25.8, 55.1, 64.3, 64.9, 76.0, 104.0; HRMS (FAB) calcd for
mmol) and palladium on carbon (10%, 5 mg) in ethanol (1 mL)
was vigorously stirred under an atmosphere of H2 at room
temperature for 2 h, the reaction mixture was filtered through
a Celite pad, and the filter cake was washed with ethanol. The
combined filtrates were concentrated to give crude N-hydroxy
derivative that was employed for the next step without further
purification.To a solution of the above N-hydroxy compound
in methanol (0.5 mL) was added NH3 (2 M solution in
methanol (1 mL). The reaction mixture was stirred for 6 h,
and the solvent was removed in vacuo to give compound 49
(15 mg, 50%) as a pale yellow solid: 1H NMR (500 MHz,
CD3OD) δ 1.36 (d, J ) 6.9 Hz, 3H), 3.63 (t, J ) 2.5 Hz, 1H),
3.81 (dq, J ) 7.0, 2.5 Hz, 1H), 4.83 (d, J ) 2.5 Hz, 1H), 7.37-
7.40 (m, 2H), 7.44-7.48 (m, 1H), 8.03-8.05 (m, 2H); HRMS
(FAB) calcd for C12H16N3O4 266.2840, found 266.2852.
Com p ou n d 50. Mercuric chloride (1.68 g, 6.19 mmol) was
added in one portion to a solution of thiourea 1416 (1.78 g, 5.62
mmol), triethylamine (2.34 mL, 16.9 mmol), and the crude
amine 43 (1.64 g, 5.62 mmol) in DMF (14 mL) at 0 °C. The
color of the reaction mixture changed to dark yellow, and the
reaction was then warmed to room temperature. After 24 h, a
combination of brine solution and EtOAc was added to the
reaction. The aqueous layer was extracted with EtOAc (3 ×
20 mL). The combined organic layers were washed with 1 M
sodium bicarbonate solution, filtered through Celite, dried with
MgSO4, and concentrated in vacuo to afford a pale yellow foam.
The crude product was purified by flash chromatography on
silica gel using hexanes/EtOAc (2:1) as eluent to give 50 (2.24
g, 69%) as a colorless foam: 1H NMR (500 MHz, CDCl3) δ 0.01
(s, 3H), 0.03 (s, 3H), 0.87 (m, 9H), 1.12 (d, J ) 6.7 Hz, 3H),
1.16 (t, J ) 7.0 Hz, 3H), 1.21 (t, J ) 7.1 Hz, 3H), 3.44-3.53
(m, 2H), 3.64-3.71 (m, 2H), 3.83 (dq, J ) 7.0, 1.5 Hz, 1H),
4.00 (dd, J ) 7.0, 2.0 Hz, 1H), 4.25 (d, J ) 7.0 Hz, 1H), 4.82
(ABq, J ) 23.0, 12.0 Hz, 2H), 5.11 (ABq, J ) 30.5, 12.0 Hz,
2H), 6.18 (bd, J ) 7.5 Hz, 1H), 7.28-7.38 (m, 10H), 7.89 (bs,
1H); 13C NMR (100 MHz, CDCl3) δ -5.1, -4.1, 13.9, 15.1, 15.4,
18.2, 26.0, 47.4, 59.0, 63.0, 67.4, 71.7, 75.6, 102.8, 127.7, 128.2,
1283, 128.4, 128.6, 128.7, 135.2, 138.0, 146.8, 152.5; HRMS
(FAB) calcd for C30H48N3O6Si 574.3312, found 574.3297.
Com p ou n d 51. Trifluoroacetic acid (8 mL) and water (800
µL) were added to a solution of compound 50 (1.82 g, 3.17
mmol) in dichloromethane (8 mL). The reaction mixture was
stirred at room temperature for 12 h, and the solvent was
removed in vacuo to give 51 (1.24 g, 78%) as a pale yellow
solid: 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 3H), 0.06 (s, 3H),
0.85 (bs, 12H), 2.68 (dq, J ) 6.7, 2.2 Hz, 1H), 3.57 (dd, J )
4.9, 2.3 Hz, 1H), 4.46 (d, J ) 9.5 Hz, 1H), 4.90 (d, J ) 3.2 Hz,
1H), 4.96 (d, J ) 9.4 Hz, 1H), 5.02 (d, J ) 12.7 Hz, 1H), 5.38
(d, J ) 12.7 Hz, 1H), 7.05-7.13 (m, 4H), 7.22-7.29 (m, 2H),
7.37 (m, 2H), 7.54 (m, 2H), 8.19 (bs, 1H); 13C NMR (125 MHz,
CDCl3) δ -5.1, -4.4, 15.8, 17.9, 25.7, 44.8, 66.0, 68.1, 77.3,
82.1, 127.6, 127.7, 128.0, 128.2, 128.3, 129.8, 134.7, 138.4,
158.2, 163.6; HRMS (FAB) calcd for C26H38N3O5Si2 500.2581,
found 500.2564.
C
15H31NO3SSiNa 356.1692, found 356.1695.
Com p ou n d 56. A mixture of isothiocyanate 49 (268 mg,
0.80 mmol) and aqueous ammonia (4 mL) in ethanol (2 mL)
was refluxed for 6 h. The reaction mixture was allowed to cool
to room temperature and was extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated in vacuo to give a pale yellow
oil. The crude product was purified by flash chromatography
on silica gel using EtOAc as an eluent to afford 56 (200 mg,
74%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.06 (s,
3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.19 (t, J ) 6.9 Hz, 6H), 1.20 (d,
J ) 6.9 Hz, 3H), 3.50-3.71 (m, 6H), 4.29 (d, J ) 6.0 Hz, 1H),
5.87 (bs, 1H), 6.31 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ -4.7,
-4.2, 15.4, 18.2, 25.9, 50.9, 62.7, 64.5, 75.5, 103.2, 181.5;
HRMS (FAB) calcd for C15H35N2O3SSi 351.2138, found 351.2132.
Com p ou n d 57. To a mixture of thiourea 56 (156 mg, 0.44
mmol), DMAP (60 mg, 0.49 mmol), and triethylamine (250 µL,
1.78 mmol) in dichloromethane (2 mL) was added a solution
of BOC2O (120 mg, 0.53 mmol) in CH2Cl2 (0.5 mL). The
reaction mixture was stirred at room temperature for 2 h. After

Synthesis of 2-Substituted Polyhydroxytetrahydropyrimidines
J . Org. Chem., Vol. 65, No. 8, 2000 2409
dilution with EtOAc (10 mL), the reaction mixture was washed
with water and brine, dried (MgSO4), concentrated, and
purified by flash chromatography on silica gel using hexanes/
EtOAc (6:4) as eluent to give 57 (190 mg, 79%) as a pale yellow
oil: 1H NMR (500 MHz, CDCl3) δ 0.14 (s, 6H), 0.93 (s, 9H),
1.23 (t, J ) 7.1 Hz, 3H), 1.25 (t, J ) 7.9 Hz, 3H), 1.28 (d, J )
7.0 Hz, 3H), 1.47 (s, 9H), 3.57-3.66 (m, 3H), 3.70-3.75 (m,
2H), 4.24 (d, J ) 7.0 Hz, 1H), 4.70 (1H, m), 7.89 (s, 1H), 10.15
(d, J ) 5.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -4.7, -4.1,
15.1, 15.2, 16.3, 18.2, 25.8, 27.9, 52.7, 64.2, 64.8, 75.1, 83.0,
104.0, 151.1, 178.0; HRMS (FAB) calcd for C20H42N2O5SSiCs
583.1638, found 583.1621.
s), 3.77 (bs, 1H), 3.82 (bs, 1H), 4.91 (bs, 1H); 13C NMR (100
MHz, CDCl3) δ -5.1, -4.8, 13.4, 14.6, 17.8, 25.4, 48.2, 66.2,
76.3, 163.8; HRMS (FAB) calcd for C12H27N2O2SSi 291.1563,
found 291.1559.
Com p ou n d 62 (12 mg, 62%): 1H NMR (500 MHz, CDCl3)
δ 0.09 (s, 3H), 0.10 (s, 3H), 0.87 (s, 9H), 1.01 (t, J ) 7.4 Hz,
3H), 1.32 (d, J ) 6.6 Hz, 3H), 1.70 (m, 2H), 3.01-3.07 (m, 1H),
3.11-3.17 (m, 1H), 3.78 (m, 1H), 3.86 (m, 1H), 4.91 (d, J ) 3.0
Hz, 1H), 8.26 (m, 1H), 10.73 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ -5.0, -4.7, 12.8, 14.8, 22.3, 25.5, 29.3, 33.2, 48.3,
66.2, 76.4, 162.8; HRMS (FAB) calcd for
319.1876, found 319.1871.
C14H31N2O2SSi
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
58-60. A solution of BOC derivative 57 (0.18-0.29 mmol) in
dry THF (1 mL) was added dropwise to a stirred suspension
of sodium hydride (95% dispersion in mineral oil, 2.1 equiv)
in THF (1 mL) at 25 °C. After 10 min, alkyl halide (1.6 equiv)
was added dropwise to the reaction mixture and the resulting
mixture stirred for 2-12 h. Excess solvent was removed in
vacuo, and the residue was dissolved in water (1 mL). The
aqueous solution was extracted with EtOAc (3 × 2 mL), and
the combined organic extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. Purification of the residue
by flash chromatography on silica gel using hexanes/EtOAc
(6:4) as eluent affords S-alkylated compound as a colorless oil.
Com p ou n d 58. According to the general procedure, 57 (128
mg, 0.29 mmol), sodium hydride (14 mg of an 95% dispersion
in mineral oil, 0.57 mmol), and iodomethane (28 µL, 0.46
mmol) gave methylsulfanyl compound 58 (98 mg, 74%):. 1H
NMR (500 MHz, CDCl3) δ 0.05 (s, 3H), 0.08 (s, 3H), 0.89 (s,
9H), 1.18 (t, J ) 7.1 Hz, 3H), 1.19 (d, J ) 7.3 Hz, 3H), 1.20 (t,
J ) 7.0 Hz, 3H), 1.44 (s, 9H), 2.40 (s, 3H), 3.48 (d, J ) 6.9 Hz,
1H), 3.52 (q, J ) 7.1 Hz, 2H), 3.65 (q, J ) 7.1 Hz, 2H), 3.95
(m, 1H), 4.19 (d, J ) 7.0 Hz, 1H), 10.05 (d, J ) 8.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ -4.8, -4.0, 13.5, 15.1, 15.3, 18.2,
18.3, 25.8, 28.1, 51.0, 64.3, 64.5, 75.7, 78.8, 103.8, 161.5, 171.4;
HRMS (FAB) calcd for C21H45N2O5SSi 465.2818, found 465.2810.
Com p ou n d 59. According to the general procedure, 57 (82
mg, 0.18 mmol), sodium hydride (9 mg of an 95% dispersion
in mineral oil, 0.36 mmol), and iodopropane (26 µL, 0.29 mmol)
gave propylsulfanyl compound 59 (65 mg, 73%): 1H NMR (400
MHz, CDCl3) δ 0.10 (s, 3H), 0.13 (s, 3H), 0.94 (s, 9H), 1.00 (t,
J ) 7.5 Hz, 3H), 1.20-1.26 (m, 6H), 1.23 (d, J ) 7.0 Hz, 3H),
1.48 (s, 9H), 1.65 (m, 2H), 3.10 (t, J ) 7.0 Hz, 1H), 3.51 (m,
4H), 3.67-3.75 (m, 3H), 4.04 (m, 1H), 4.24 (d, J ) 7.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ -4.8, -4.0, 15.1, 15.3, 18.2, 22.2,
25.8, 28.2, 32.5, 54.0, 64.3, 64.7, 74.5, 75.7, 78.7, 103.5, 161.6,
171.3; HRMS (FAB) calcd for C23H48N2O5SSi 493.3131, found
493.3114.
Com p ou n d 60. According to the general procedure, 57 (100
mg, 0.22 mmol), sodium hydride (11 mg of an 95% dispersion
in mineral oil, 0.44 mmol), and benzyl bromide (12 µL, 0.10
mmol) gave benzylsulfanyl compound 60 (68 mg, 57%): 1H
NMR (400 MHz, CDCl3) δ 0.08 (s, 3H), 0.10 (s, 3H), 0.94 (s,
9H), 1.16-1.26 (m, 9H), 1.52 (s, 9H), 3.49-3.61 (m, 3H), 3.66-
3.77 (m, 2H), 3.98 (m, 1H), 4.23 (d, J ) 7.0 Hz, 1H), 4.35 (s,
2H), 7.26-7.36 (m, 5H), 10.10 (d, J ) 8.5 Hz, 1H); HRMS
(FAB) calcd for C27H48N2O5SSiCs 673.2108, found 673.2128.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
61-63. Trifluoroacetic acid (1 mL) and water (100 µL) were
added to a solution of compounds 58-60 (0.06-0.14 mmol) in
dichloromethane (1 mL). The reaction mixture was stirred at
room temperature for 12 h, and excess solvents were removed
in vacuo to give compounds 61-63 as a colorless foam.
Com p ou n d 61 (32 mg, 76%): 1H NMR (500 MHz, CDCl3)
δ 0.09 (s, 6H), 0.87 (s, 9H), 1.32 (d, J ) 7.5 Hz, 3H), 2.58 (3H,
Com p ou n d 63 (19 mg, 54%): 1H NMR (500 MHz, CDCl3)
δ 0.04 (s, 3H), 0.05 (s, 3H), 0.81 (s, 9H), 1.23 (d, J ) 6.7 Hz,
3H), 3.74 (m, 1H), 3.80 (m, 1H), 4.33 (s, 2H), 4.90 (m, 1H),
7.25-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.1, -4.8,
14.6, 25.5, 29.7, 35.6, 48.3, 66.2, 76.4, 128.5, 129.0, 129.1, 133.2,
162.3; HRMS (FAB) calcd for C18H31N2O2SSi 367.1876, found
367.1871.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
64-66. To a solution of silyl ether 61-63 (0.04-0.11 mmol)
in acetonitrile (1 mL) was added aqueous HF (49% in water,
0.2 mL). The reaction mixture was stirred for 2 h, and the
solvent was removed in vacuo. The residue was purified by
passing through a short C-18 column using water as an eluent
to afford compounds 64-66 as white solids.
Com p ou n d 64 (12 mg, 62%): 1H NMR (500 MHz, D2O) δ
1.22 (d, J ) 7.0 Hz, 3H), 2.47 (s, 3H), 3.71 (dq, J ) 14.0, 7.0,
2.6 Hz, 1H), 3.77 (t, J ) 2.6 Hz, 1H), 4.83 (d, J ) 3.0 Hz, 1H);
13C NMR (100 MHz, D2O) δ 13.5, 14.3, 48.0, 65.5, 75.6, 165.7;
HRMS (FAB) calcd for C6H13N2O2S 177.0698, found 177.0700.
Com p ou n d 65 (4 mg, 52%): 1H NMR (500 MHz, D2O) δ
0.87 (t, J ) 7.4 Hz, 3H), 1.23 (d, J ) 6.9 Hz, 3H), 1.58 (m,
2H), 3.00 (m, 2H), 3,73 (dd, J ) 7.0, 2.5 Hz, 1H), 3.79 (t, J )
2.5 Hz, 1H), 4.83 (d, J ) 2.5 Hz, 1H); 13C NMR (100 MHz,
D2O) δ 12.9, 14.2, 22.7, 33.8, 48.1, 65.4, 75.6, 164.5; HRMS
(FAB) calcd for C8H17N2O2S 205.1011, found 205.1008.
Com p ou n d 66 (8 mg, 61%): 1H NMR (500 MHz, D2O) δ
1.17 (d, J ) 6.8 Hz, 3H), 3.60 (q, J ) 7.1, 3.9 Hz, 1H), 3.70 (m,
1H), 4.28 (s, 2H), 4.76 (m, 1H), 7.24-7.32 (m, 5H); HRMS
(FAB) calcd for C12H17N2O2S 253.1011, found 253.1010.
Cr ysta llogr a p h ic Da ta .20 Compounds 12, 17, and 51
crystallized as thin, colorless plates. X-ray data were collected
and recorded with a Rigaku AFC6R diffractometer. Com-
pounds 12 and 51 formed monoclinic crystals, space group
P21/c with Z ) 4. Compounds 17 formed orthorhombic crystals,
space group P212121 with Z ) 4. The structures were solved
by means of the SHELXS8621 direct methods package and
refined on F by the full-matrix least-squares method, allowing
anisotropic displacement parameters for non-hydrogen atoms.
Hydrogen atoms were introduced in calculated positions and
were refined.
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, 11, 12, 15-40, 42, 44-53, and 55-
66. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O9915574
(20) Crystallographic data for the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-100368. Copies of the data
can be obtained free of charge on application to The Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, U.K. (Fax: Int. code +(1223)-
336-033; e-mail: deposit@chemcrys.cam.ac.uk).
(21) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467-473.