Introduction of a carbohydrate moiety into the structure of thiourea compounds targeting HIV-1 reverse transcriptase

Article abstract of DOI:10.1081/SCC-120017195

We developed a novel approach to introduce a carbohydrate moiety into the structure of thiourea compounds targeting the NNI binding pocket of the HIV-1 reverse transcriptase. The described method involves the synthesis of an amino-substituted carbohydrate moiety which is then condensed with various thiocarbonylimidazole derivatives of substituted aromatic amines.

Full text of DOI:10.1081/SCC-120017195

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Introduction of a Carbohydrate Moiety into the
Structure of Thiourea Compounds Targeting HIV-1
Reverse Transcriptase
P. Mallikarjun Goud a , T. K. Venkatachalam a & F. M. Uckun M.D., Ph.D. a
a Department of Chemistry , Parker Hughes Institute , Roseville, Minnesota, USA
Published online: 21 Aug 2006.
To cite this article: P. Mallikarjun Goud , T. K. Venkatachalam & F. M. Uckun M.D., Ph.D. (2003) Introduction of a
Carbohydrate Moiety into the Structure of Thiourea Compounds Targeting HIV-1 Reverse Transcriptase, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:7, 1185-1193, DOI:
10.1081/SCC-120017195
To link to this article: http://dx.doi.org/10.1081/SCC-120017195
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1185–1193, 2003
Introduction of a Carbohydrate Moiety into the
Structure of Thiourea Compounds Targeting
HIV-1 Reverse Transcriptase
P. Mallikarjun Goud, T. K. Venkatachalam, and
*
F. M. Uckun
Department of Chemistry, Parker Hughes Institute,
Roseville, Minnesota, USA
ABSTRACT
We developed a novel approach to introduce a carbohydrate moiety
into the structure of thiourea compounds targeting the NNI binding
pocket of the HIV-1 reverse transcriptase. The described method
involves the synthesis of an amino-substituted carbohydrate moiety
which is then condensed with various thiocarbonylimidazole
derivatives of substituted aromatic amines.
*Correspondence: Fatih Uckun, M.D., Ph.D., Parker Hughes Cancer Center,
2699 Patton Road, Roseville, MN 55113. Fax: 651-796-5493. E-mail: fatih_
uckun@ih.org.
1185
DOI: 10.1081/SCC-120017195
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1186
Goud, Venkatachalam, and Uckun
INTRODUCTION
The reverse transcriptase (RT) enzyme of the human immunodefi-
ciency virus (HIV-1) is responsible for the reverse transcription of
retroviral RNA to proviral DNA.[1] Because of its pivotal role in
HIV-1 replication, RT serves as a molecular target for drugs aimed at
treating AIDS.[2] We have previously reported the structure-based design
of several thiourea compounds (Z, Fig. 1) as promising non-nucleoside
inhibitors (NNI) of RT.[3–11] Although these thiourea derivatives are
potent anti-HIV agents, theirpoorbioavailability limits theirtherapeutic
potential. In order to eliminate this disadvantage, we have developed a
synthetic strategy for introduction of a carbohydrate side chain which
may improve the bioavailability of thiourea derivatives. This strategy
may also result in increased intracellular concentrations of the thiourea
compounds.
RESULTS AND DISCUSSION
Synthesis of several new carbohydrate-containing thiourea
compounds, was initiated using several water soluble secondary amines
prepared from D-glucose. In order to prepare water soluble chiral amines
of furanosaccharides, diacetone-D-glucose was chosen as the starting
material 1, which was prepared from D-glucose and acidic (H2SO4)
acetone, as described in the literature.[12] The crystalline furano sugar 1
on benzylation with NaH-BnBr-DMF at 0ꢀC gave benzyl ether 2 with a
92% yield. Regioselective hydrolysis of 1,2 with 0.8% H2SO4 yielded diol
(3,4) which was oxidatively cleaved with sodium metaperiodate to yield
aldehydes which on immediate reaction with fluorophenethyl amine in
CH2Cl2/Na2SO4 yielded the corresponding imines. These imines without
isolation were immediately reduced with NaBH4–MeOH at 0ꢀC to obtain
the corresponding secondary amines (5,6) (Sch. 1).
Figure 1.

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Carbohydrate Moiety and HIV-1 RT
1187
Substituted pyridyl thiocarbonylimidazole derivaties were prepared
using the respective primary amines and thiocarbonyldiimidazole in
acetonitrile at room temperature for 48 h (Sch. 2). The condensation
of secondary amines (5,6) with appropriately substituted pyridyl
thiocarbonylimidazole derivatives in DMF at 90ꢀC for15 h and
workup furnished the final products (7–12).
CONCLUSION
We have developed an efficient method forthe intorduction of a
carbohydrate moiety into the structure of thiourea compounds with anti-
Scheme 1. Reagents and conditions: (a) CH3COCH3, H2SO4/0ꢀC; (b) NaH,
DMF, BnBr, 0ꢀC; (c) 0.8% H2SO4, MeOH, r.t., 3 h; (d) NaIO4, CH2Cl2, Satd.
NaHCO3, 0ꢀC, 2 h; (e) fluorophenethyl amine, CH2Cl2, r.t., 1 h; (f) NaBH4,
MeOH, 12 h.
Scheme 2. Reagents and conditions: (a) acetonitrile/N2, r.t., 48 h; (b) DMF,
90ꢀC, 15 h.

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1188
Goud, Venkatachalam, and Uckun
HIV activity. It is hoped that improved in vivo efficacy may be observed
for these derivatives due to increased bioavailability and improved cellular
uptake. Further work is in progress to evaluate the biological activity as
well as bioavailability of these novel furanosyl thioureas.
EXPERIMENTAL
3-O-benzyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (2). To a
solution of 1,2:5,6-di-O-isopropylidine-a-D-glucofuranose (1) (6.0 g,
23.0 mmol) in dimethylformamide (40 mL) was added sodium hydride
(1.33 g, 55.1 mmol) at 0ꢀC. After stirring for 15 min benzyl bromide
(5.1 g, 30.0 mmol) was added and further stirred for 30 min. After this
period, the excess sodium hydride was quenched with methanol (1 mL)
and the resulting mixture was poured into ice cold water and extracted
with ether(2 ꢁ 100 mL). The organic layer was washed with additional
water and the ether layer dried over anhydrous magnesium sulfate.
Concentration of solvent and purification by silica gel chromatography
(hexane/ethylacetate, 5:1) gave the title compound as a colorless oil
(7.55 g, 94%). 1H NMR (CDCl3) d: 7.45–7.22 (m, 5H, ArH), 5.85
(d, 1H, J ¼ 3.8 Hz, H-1), 4.76–4.25 (m, 5H, H-3-6, 6[1]), 4.15–3.19
(m, 3H, H-2, OCH2Ph), 1.50, 1.44, 1.36, 1.31 (4s, 12H, 4 ꢁ CH3);
LCMS (ESI) calcd. for(M þH): 351.4, Found: 351.2; Anal. calcd.
forC 19H26O6: C, 65.13; H, 7.48. Found: C, 65.09; H, 7.45.
3-O-benzyl-1,2-O-isopropylidene-a-D-glucofuranose (3). A solution of
compound (2) (7.0 g, 20.0 mmol) in methanol (40 mL) and 0.8% aqueous
sulfuric acid (40 mL) was stirred for 12 h. After completion of the
reaction as evidenced by TLC, solid barium carbonate was added to the
reaction mixture and the pH was adjusted to 7.0. The solid mass obtained
was filtered off and the filtrate concentrated in vaccuum to yield a viscous
liquid which was chromatographed (hexane/ethylacetate, 3:7) to furnish
the title compound as a syrup (5.4 g, 87%). [a]D ¼ À 39.4ꢀ(c 1.0, CHCl3);
1H NMR (CDCl3) d: 7.45–7.22 (m, 5H, ArH), 5.9 (d, 1H, J ¼ 3.8 Hz,
H-1), 4.72 (d, 1H, J ¼ 11.5 Hz, OCH2Ph), 4.58 (d, 1H, J ¼ 3.8 Hz, H-2),
4.52 (d, 1H, J ¼ 11.2 Hz, OCH2Ph), 4.14–3.6 (m, 5H, H-3-6, 6[1]), 2.45
(brs, 1H, OH), 1.48, 1.3 (2s, 6H, 2 ꢁ CH3); LCMS (ESI) calcd.
for(M þH): 311.34, Found: 311.35; Anal. calcd. forC 16H22O6: C,
61.92; H, 7.15. Found: C, 61.89; H, 7.11. (Lit.[13] C, 61.99; H, 7.19).
1,2-O-isopropylidene-a-D-glucofuranose (4). Compound 4 was pre-
pared from 1 (5 g, 19.2 mmol) in methanol (40 mL) and 0.8% aqueous
sulfuric acid (40 mL) as described for compound 3: (3.6 g, 92%) as a solid.

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Carbohydrate Moiety and HIV-1 RT
1189
M.p.: 159–160ꢀC; [a]D ¼ À13.5ꢀ(c 1.0, H2O); 1H NMR (D2O) d: 5.86–5.85
(d, 1H, J ¼ 3.6 Hz, H-1), 4.54–4.53 (d, 1H, J ¼ 3.6 Hz, H-2), 4.16–4.15
(d, 1H, J ¼ 2.4 Hz, H-3), 3.92–3.91 (d, 1H, J ¼ 2.4 Hz, H-4), 3.41–3.74
(m, 3H, H-5,6,6[1]), 1.35, 1.20 (2s, 2 ꢁ CH3); LCMS (ESI) calcd. for
(MþH): 221.2, Found: 221.3; Anal. calcd. forC H16O6: C, 49.09; H,
9
7.32. Found: C, 49.28; H, 7.39. (Lit.[13] C, 49.26; H, 7.44).
[((4S,1R,5R)-7,7-dimethyl–2,6,8-trioxa–4-phenoxybicyclo [3.3.0] oct-
3yl) methyl] [2-(2-flurophenyl] amine (5). To a solution of diol 3 (8 g,
25.8 mmol) in dichloromethane and saturated sodium bicarbonate solu-
tion (4.0 mL) was added sodium metaperiodate (11.0 g, 53.2 mmol) at 0ꢀC
and stirred for 2 h at room temperature. After completion of the reaction
anhydrous sodium sulphate (20 g) was added to the reaction mixture,
filtered and filterate concentrated to obtain the aldehyde (5.8 g, 82%) as
a syrup. To a solution of aldehyde (5.8 g, 22.1 mmol) and fluorophenethyl-
amine (3.07 g, 22.1 mmol) in dichloromethane (20 mL) was added anhy-
drous sodium sulphate (10 g) and stirred vigorously for 30 min. After
completion of the reaction , it was filtered off and filtrate concentrated
to obtain imine (7.0 g, 18.2 mmol) which was dissolved in methanol
(20 mmol) and sodium borohydride (1.69 g, 45.6 mmol) was added at
0ꢀC. Reaction was monitored by TLC, after completion of the reaction,
methanol was removed under reduced pressure to obtain a residue which
was dissolved in ethylacetate (150 mL), washed with saturated sodium
chloride solution (2 ꢁ 50 mL), dried and concentrated to obtain a
syrupy residue which was purified by silica gel (60–120 mesh, hexane:
EtOAc, 1:1) to obtain the title compound 5 (5.6 g, 80%) as a colorless
1
syrup. H NMR (CDCl3) d: 7.33–6.98 (m, 9H, ArH), 5.90–5.89 (d, 1H,
J ¼ 3.3 Hz, H-1), 4.73–4.69 (d, 1H, J ¼ 12 Hz, OCH2Ph), 4.68–4.67 (d, 1H,
J ¼ 3.6 Hz, H-5), 4.53–4.49 (d, 1H, J ¼ 11.7 Hz, OCH2Ph), 4.42–4.38 (m,
1H, H-3), 3.99–3.98 (d, 1H, J ¼ 3 Hz, H-4), 2.99–2.74 (m, 6H, N-CH2-
Sug, Ar-CH2-CH2-N), 1.48, 1.32 (2s, 6H, 2 ꢁ CH3); LCMS (ESI) calcd.
for(M þH) 389.46, Found: 389.48; Anal. calcd. forC 22H27FNO4: C,
68.02; H, 7.0; N, 3.6. Found: C, 68.0; H, 6.99; N, 3.56.
(2S, 1R, 5R)-3-({[2-(-fluorophenyl) ethyl]amino} methyl)-7,7-dimethyl-
4,6,8-trioxa bicyclo [3.3.0] octan-2-ol (6). Compound 6 was prepared from
4 (3.5 g, 15.9 mmol), saturated sodium bicarbonate (3.0 mL), sodium per-
iodate (6.7 g, 31.8 mmol) anhydrous sodium sulphate (10 g), fluorophen-
ethylamine (3.2 g, 23.0 mmol and sodium borohydride (0.74 g, 19.6 mmol)
as described for compound 5: (4.4 g, 83%) as a semisolid: 1H NMR
(CDCl3) d: 7.24–6.98 (m, 4H, ArH), 5.90–5.89 (d, 1H, J ¼ 3.3 Hz, H-5),
4.56–4.43 (d, 1H, J ¼ 3.9 Hz, H-1), 4.23–4.15 (m, 2H, H-2,3), 2.96–2.77
(m, 6H, N-CH2-Sug, Ar-CH2-CH2-N), 1.44, 1.28 (2s, 6H, 2 ꢁ CH3);
LCMS (ESI) calcd. for(M þH) 312.35, Found: 312.36; Anal. calcd. for

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1190
Goud, Venkatachalam, and Uckun
C16H22FNO4: C, 61.72; H, 7.12; N, 4.49. Found: C, 61.65; H, 7.01;
N, 4.31.
Preparation of Thiocarbonylimidazole Derivatives of
PyridylCompounds
In a 500 mL RB flask undernitrogen was added 8.6 g (50 mmol) of
substituted-2-aminopyridine and 250 mL of anhydrous acetonitrile. The
contents were stirred at room temperature and 1.1 Eq. of 1,10-thiocarbo-
nyldiimidazole was introduced. The contents were allowed to stir for 48 h
when a precipitate appeared. The precipitate was filtered and washed
with dry acetonitrile (2 ꢁ 50 mL), dried under vaccum to furnish the
required thiocarbonylimidazole derivative as a crisp solid (95%). This
was used as such without further purification in the next step.
General Procedure for the Synthesis of Halo Pyridyl-
Fluorophenethyl-a-D-Glucofuranosyl Thioureas (7–12)
To a stirred solution of secondery amine in dimethyl formamide
(20 mL) was added 1.2 Eq. of the respective pyridyl thiocarbonylimidazole
precursor and the contents were heated to 90ꢀC for15 h overan oil bath.
The mixture was cooled to room temperature and poured into crushed ice
cold waterto obtain a precipitate which was filtered, washed with water
(2 ꢁ 50 mL) and dried under vacuum. The solid was then extracted with
chloroform, washed successively with brine, water and the resulting
organic layer was dried over anhydrous magnesium sulfate. Filtration
and evaporation of the solvent gave crude glucofuranosyl thioureas.
The crude material was subjected to column chromatography over silica
gel (hexane/ethylacetate 7:3) to obtain analytical pure sample of the
thioureas in 75–80% yield as light yellow solids and semi solids.
(2S,1R,5R) - 3- [({[(5-bromo(2-pyridyl))amino]thioxomethyl}[2 -fluoro-
phenyl) ethyl] amino)methyl]- 7, 7-dimethyl-4,6,8-trioxabicyclo [3.3.0]
octan-2-ol(7). [a]D ¼ À0.045ꢀ(c 1, MeOH); M.p.: 74–75ꢀC; 1H NMR
(CDCl3) d: 9.6 (brs, 1H, NH), 8.19 (m, 2H, ArH), 7.76–7.72 (dd, 1H,
J ¼ 2.4, 2.1 Hz, ArH), 7.32–6.90 (m, 4H, ArH), 5.90–5.89 (d, 1H,
J ¼ 3.3 Hz, H-5), 4.56–4.55 (d, 1H, J ¼ 2.7 Hz, H-1), 4.33–3.64 (m, 6H,
–CH2-N-CH2-, H-2,3), 3.16–3.14 (m, 2H, Ar-CH2, –CH2-N), 1.40, 1.25
(2s, 6H, 2 ꢁ CH3); 13C NMR (CDCl3) d: 180.8, 162.6, 159.4, 152.1, 147.8,
139.9, 131.1, 128.5, 124.3, 119.5, 115.4, 115.1, 112.0, 104.4, 85.0, 78.0,
73.8, 52.4, 49.2, 26.7, 26.5; LCMS (ESI) calcd. for(M þH) 526.07,

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Carbohydrate Moiety and HIV-1 RT
1191
Found: 526.0; HPLC Rt: 9.14 min, % purity 97.1; Anal. calcd. for
C22H25BrFN3O4S: C, 50.2; H, 4.79; N, 7.98 Found: C, 49.66; H, 4.80;
N, 8.03.
({[(4S, 1R, 5R)-7,7-dimethyl-2, 6, 8-trioxa-4-(phenylmethoxy) bicyclo
oct-3-yl]methyl}[2-(2-fluorophenyl)ethyl]amino[(5-bromo(2-pyri-
[3.3.0]
dyl)amino] methane-1-thione (8). [a]D ¼ À0.074ꢀ(c 1, MeOH); M.p.:
64–65ꢀC; H NMR (CDCl3) d: 9.10 (brs, 1H, NH), 8.30–8.27 (m, 2H,
1
ArH), 7.73–7.69 (dd, 1H, J ¼ 2.7 Hz, 2.1 Hz, ArH), 7.40–6.99 (m, 9H,
ArH), 6.10–6.08 (d, 1H, J ¼ 3.9 Hz, H-1), 4.73–4.69 (d, 1H, J ¼ 12 Hz,
OCH2Ph), 4.68–4.67 (d, 1H, J ¼ 3.6 Hz, H-5), 4.53–4.49 (d, 1H,
J ¼ 11.7 Hz, OCH2Ph), 4.43–3.65 (m, 6H, H-3,4, CH2-N-CH2),
3.19–3.07 (m, 2H, Ar-CH2, –CH2-N), 1.48, 1.32 (2s, 6H, 2 ꢁ CH3);
13C NMR (CDCl3): 181.0, 162.5, 159.3, 152.1, 148.4, 138.8, 136.6,
131.2, 131.2, 128.5, 128.3, 128.2, 128.1, 127.6, 125.1, 124.3, 117.6,
115.2, 115.0, 113.9, 112.0, 105.0, 82.0, 78.7, 71.8, 52.5, 51.2, 26.7, 26.2;
LCMS (ESI) calcd. for(M þH) 617.5, Found: 617.2; HPLC Rt: 13.6 min,
% purity 99.8; Anal. calcd. for C29H31BrFN3O4S: C, 56.50; H, 5.07; N,
6.82 Found: C, 56.14; H, 5.09; N, 6.84.
({[(4S, 1R, 5R)-7,7-dimethyl-2, 6, 8-trioxa-4-(phenylmethoxy) bicyclo
[3.3.0] oct-3-yl] methyl}[2-(2-fluorophenyl)ethyl] amino[(5-chloro(2-pyridyl)
amino] methane-1-thione (9). [a]D ¼ À0.077ꢀ(c 1, MeOH); M.p.: 59–60ꢀC;
1H NMR (CDCl3) d: 9.14 (brs, 1H, NH), 8.31–8.28 (d, 1H, J ¼ 9 Hz,
ArH), 8.18–8.17 (d, 1H, J ¼ 2.4 Hz, ArH), 7.58–7.55 (dd, 1H, J ¼ 2.4,
2.7 Hz, ArH), 7.38–6.97 (m, 9H, ArH), 6.08–6.07 (d, 1H, J ¼ 3.6 Hz,
H-1), 4.71–4.67 (d, 1H, J ¼ 11.7 Hz, OCH2Ph), 4.66–4.65 (d, 1H,
J ¼ 3.9 Hz, H-5), 4.51–4.47 (d, 1H, 11.7 Hz, OCH2Ph), 4.42–3.63 (m,
6H, H-3,4, CH2-N-CH2), 3.22–3.03 (m, 2H, Ar-CH2, –CH2-N), 1.45,
1.30 (2s, 6H, 2 ꢁ CH3); 13C NMR (CDCl3) d: 181.1, 162.5, 159.3, 151.7,
146.1, 136.6, 136.2, 131.3, 128.5, 128.4, 128.3, 128.1, 127.7, 125.9, 124.2,
117.2, 115.3, 115.0, 112.1, 105.0, 82.0, 81.7, 78.7, 71.8, 52.5, 51.2, 26.7,
26.2; LCMS (ESI) calcd. for(M þH) 572.1, Found: 572.2; HPLC
Rt: 34.1 min, % purity 96.3; Anal. calcd. for C29H31ClFN3O4S: C,
60.89; H, 5.46; N, 7.34. Found: C, 60.52; H, 5.52; N, 7.54.
({[(4S, 1R, 5R)-7,7-dimethyl-2, 6, 8-trioxa-4-(phenylmethoxy) bicyclo
[3.3.0] oct-3-yl] methyl}[2-(2-fluorophenyl)ethyl] amino[(5-methyl(2-pyri-
dyl) amino] methane-1-thione (10). [a]D ¼ À0.053ꢀ (c 1, MeOH); M.p.:
50–52ꢀC; H NMR (CDCl3): 8.78 (brs, 1H, ArH), 8.03 (brs, 2H, ArH),
1
7.45–7.41 (dd, 1H, J ¼ 2.1, 2.4 Hz, ArH), 7.37–696 (m, 9H, ArH),
6.04–6.03 (d, 1H, J ¼ 3.9 Hz, H-1), 4.70–4.66 (d, 1H, J ¼ 12 Hz,
OCH2Ph), 4.63–4.62 (d, 1H, J ¼ 3.9 Hz, H-5), 4.53–4.49 (d, 1H,
11.7 Hz, OCH2Ph) 420–3.73 (m, 6H, H-3,4, CH2-N-CH2), 3.21–3.06
(m, 2H, Ar-CH2, –CH2-N), 2.52 (s, 3H, Ar-CH3), 1.45, 1.29 (2s, 6H,

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1192
Goud, Venkatachalam, and Uckun
2 ꢁ CH3); 13C NMR (CDCl3) d: 181.1, 162.6, 159.4, 136.8, 131.3, 131.2,
128.5, 128.2, 128.1, 128.0, 127.0, 124.2, 115.2, 114.9, 111.9, 105.0, 82.2,
81.8, 79.0, 71.8, 52.3, 51.0, 26.8, 26.2, 17.8; LCMS (ESI) calcd. for
(MþH) 552.68, Found: 552.2; HPLC Rt: 24.6 min, % purity 99.7;
Anal. calcd. forC 30H34FN3O4S: C, 65.32; H, 6.21; N, 7.62. Found: C,
65.20; H, 6.27; N, 7.58.
({[(4S, 1R, 5R)-7,7-dimethyl-2, 6, 8-trioxa-4-(phenylmethoxy) bicyclo
[3.3.0] oct-3-yl] methyl}[2-(2-fluorophenyl)ethyl] amino[(6-methyl(2-pyri-
dyl) amino] methane-1-thione (11). [a]D ¼ À0.047ꢀ (c 1, MeOH); M.p.:
57–58ꢀC; H NMR (CDCl3): 7.51–6.68 (m, 11H, ArH), 6.68 (brs, 1H,
1
ArH), 6.0–5.99 (d, 1H, J ¼ 3 Hz, H-1), 4.70–4.66 (d, 1H, J ¼ 12 Hz,
OCH2Ph), 4.63–4.61 (d, 1H, J ¼ 3.9 Hz, H-5), 4.56–4.52 (d, 1H,
J ¼ 12 Hz, OCH2Ph), 4.11–3.75 (m, 6H, H-3,4, CH2-N-CH2), 3.22–3.12
(m, 2H, Ar-CH2, –CH2-N), 2.40 (s, 3H, Ar-CH3), 1.45, 1.25 (2s, 6H,
2 ꢁ CH3); 13C NMR (CDCl3) d: 181.1, 162.6, 159.4, 136.9, 131.3,
128.4, 128.1, 127.9, 127.6, 124.1, 115.2, 114.9, 111.8, 104.9, 82.2, 81.6,
77.4, 76.5, 71.8, 52.1, 50.9, 26.8, 26.3, 22.5; LCMS (ESI) calcd. for
(MþH) 552.68, Found: 552.2; HPLC Rt: 27.8 min, % purity 99.6;
Anal. calcd. forC 30H34FN3O4S: C, 65.32; H, 6.21; N, 7.62. Found: C,
65.16; H, 6.32; N, 7.52.
(2S,1R,5R)-3-[({[(5-methyl(2-pyridyl))amino]thioxomethyl}[2-fluoro-
phenyl) ethyl] amino)methyl]-7,7-dimethyl-4,6,8-trioxabicyclo [3.3.0] octan-
2-ol (12). [a]D ¼ À0.045ꢀ (c 1, MeOH); M.p.: 74–75ꢀC; 1H NMR (CDCl3):
9.52 (brs, 1H, ArH), 8.13 (m, 2H, ArH), 7.74–7.70 (dd, 1H, J ¼ 2.4,
2.1 Hz, ArH), 7.22–6.89 (m, 4H, ArH), 5.90–5.89 (d, 1H, J ¼ 3.3 Hz,
H-5), 4.56–4.55 (d, 1H, J ¼ 2.7 Hz, H-1), 4.29–3.72 (m, 6H, H-2,3,
CH2-N-CH2), 3.20–3.12 (m, 2H, Ar-CH2, –CH2-N), 2.38 (s, 3H, Ar-
CH3), 1.39, 1.27 (2s, 6H, 2 ꢁ CH3); 13C NMR (CDCl3) d: 180.8, 162.6,
159.4, 152.1, 147.8, 139.9, 131.1, 128.5, 124.3, 119.5, 115.4, 115.1, 112.0,
104.4, 85.0, 73.8, 52.4, 49.2, 26.7, 26.5, 18.2; LCMS (ESI) calcd. for
(MþH) 462.56, Found: 462.52; HPLC Rt: 10.2 min, % purity 99.1;
Anal. calcd. forC 23H28FN3O4S: C, 59.85; H, 6.11; N, 9.11. Found: C,
59.78; H, 6.07; N, 9.03.
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Received in the USA May 15, 2002

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