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E. Elhalem et al. / Tetrahedron 66 (2010) 3332–3340
3.39 (s, 3H, OCH3), 3.47 (d, J¼11.5 Hz, 1H, BnOCHaH), 3.57 (t,
J¼4.6 Hz, 2H, CH2OCH3), 3.60 (s,1H, H-1), 3.67 (dt, J¼11.3, 4.8 Hz,1H,
OCHaHCH2), 3.83 (dt, J¼11.3, 4.8 Hz, 1H, OCHbHCH2), 4.22 (d,
J¼5.5 Hz, 1H, H-4), 4.25 (d, J¼11.5 Hz, 1H, BnOCHbH), 4.38 (dt, J¼8.1,
1.0 Hz,1H, H-2), 4.47 (d, J¼11.5 Hz,1H, PhCHaHO), 4.54 (d, J¼12.1 Hz,
1H, PhCH0aHO), 4.59 (d, J¼11.7 Hz,1H, PhCHbHO), 4.65 (d, J¼12.1 Hz,
1H, PhCH0bHO), 4.79 (d, J¼7.1 Hz,1H, OCHaHO), 4.83 (d, J¼7.1 Hz,1H,
OCHaHO), 7.27–7.33 (m, 10H, aromatic protons); 13C NMR
(BnOCH2), 71.7 (OCH2CH2), 72.0 (PhCH2O), 73.6 (PhCH2O), 81.5 (C-
5), 81.9 (C-3), 94.7 (OCH2O), 98.7 (C-2), 127.5 (Ph), 127.6 (Ph), 127.66
(Ph),127.68 (Ph), 128.4 (Ph), 137.6 (Ph), 137.9 (Ph),193.3 (CH3C(O)S);
HRMS (ESI) Calcd for (C27H36NaO9S2) [MþNa]þ: 591.1698; found
591.1679.
3.1.14. (1S,2S,4S,5R)-4-((2-methoxyethoxy)methoxy)-2-(benzyloxy)-
1-((benzyloxy)methyl)-6-thiabicyclo[3.1.0]hexane (37). To a solution
of 360 (448 mg, 0.8 mmol) in a mixture of ethanol–tetrahydrofu-
ran–water (5:3:1; 16 mL) was added sodium bicarbonate (133 mg,
1.6 mmol). The reaction mixture was refluxed for 13 h. The solvent
was evaporated and the residue was partitioned between water
(10 mL) and methylene chloride (10 mL). The organic phase was
washed with water (2ꢃ10 mL), dried (MgSO4), and the solvent was
evaporated. The residue was purified by column chromatography
(silica gel) eluting with hexane–EtOAc (19:1) to afford 146 mg (43%
(125.77 MHz, CDCl3) d 32.6 (C-3), 59.0 (OCH3), 60.0 (CH2OCH3), 65.6
(C-5), 66.5 (BnOCH2), 66.9 (C-2), 71.7 (OCH2CH2), 72.0 (PhCH2O),
73.2 (PhCH2O), 77.0 (C-2), 77.2 (C-4), 95.3 (OCH2O), 127.6 (Ph), 127.7
(Ph), 127.8 (Ph), 128.4 (Ph), 128.4 (Ph), 137.97 (Ph), 138.03 (Ph); MS
(m/z, relative intensity) 339 ([MꢁCH3OCH2CH2OH]þ,1), 105 (79), 91
(100), 89 (84). HRMS (ESI) Calcd for (C24H30O6Na) [MþNa]þ:
437.1940; found 437.1921.
3.1.12. S-(1R,2R,3S,5S)-5-((2-Methoxyethoxy)methoxy)-3-(benz-
yield) of pure compound 37 as a colorless oil: Rf 0.60 (hexane–
23
yloxy)-2-((benzyloxy)methyl)-2-hydroxycyclopentyl
ethanethioate
EtOAc, 3:2); [
a
]
D
þ21.5 (c 0.9, CHCl3); 1H NMR (500.13 MHz, CDCl3)
(35). To a solution of 34 (835 mg, 2.0 mmol) in anhydrous N,N-
dimethylformamide (20 mL) was added potassium thioacetate
(7.00 g, 60 mmol). The mixture was stirred at 60 ꢀC for 25 h. Then, an
aqueous saturated solution of sodium bicarbonate (10 mL) was added
and the mixture was extracted with methylene chloride (3ꢃ15 mL).
The combined organic phases were washed with water (2ꢃ5 mL),
dried (MgSO4), and the solvent was evaporated. The product was
purified bycolumnchromatography(silicagel)elutingwitha mixture
d
1.92 (ddd, J¼13.8, 8.6, 5.2 Hz, 1H, H-3a), 1.99 (dd, J¼13.8, 7.3 Hz,
1H, H-3b), 3.30 (br s, 1H, H-5), 3.37 (s, 3H, OCH3), 3.48 (d, J¼10.7 Hz,
1H, BnOCHaH), 3.49 (m, 2H, CH2OCH3), 3.60 (ddd, J¼10.9, 5.6,
3.7 Hz, 1H, OCHaHCH2), 3.73 (ddd, J¼10.9, 5.7, 3.5 Hz, 1H,
OCHbHCH2), 4.16 (d, J¼10.8 Hz, 1H, BnOCHbH), 4.31 (d, J¼5.0 Hz, 1H,
H-4), 4.49 (d, J¼11.9 Hz, 1H, PhCHaHO), 4.58 (d, J¼12.1 Hz, 1H,
PhCH0aHO), 4.60 (d, J¼12.0 Hz, 1H, PhCHbHO), 4.63 (d, J¼12.2 Hz,
1H, PhCH0bHO), 4.70 (dd, J¼8.5, 7.3 Hz, 1H, H-2), 4.76 (d, J¼7.1 Hz,
1H, OCHaHO), 4.78 (d, J¼7.1 Hz, 1H, OCHbHO), 7.26–7.35 (m, 10H,
of hexane–EtOAc (4:1) to afford 850 mg (85% yield) of pure 35 as
23
a colorless oil: Rf 0.50 (hexane–AcOEt, 1:1); [
a
]
þ14.5 (c 1.0, CHCl3);
aromatic protons); 13C NMR (125 MHz, CDCl3)
d 34.0 (C-3), 45.9 (C-
D
1H NMR (500.13 MHz, CDCl3)
d
2.12 (ddd, J¼13.9, 6.5, 5.5 Hz,1H, H-4a),
5), 55.6 (C-1), 59.0 (OCH3), 67.0 (CH2OCH3), 71.5 (BnOCH2), 71.6
(OCH2CH2), 72.3 (PhCH2O), 72.8 (PhCH2O), 77.3 (C-4), 78.2 (C-2),
94.9 (OCH2O), 127.6 (Ph), 127.6 (Ph), 127.7 (Ph), 127.7 (Ph), 128.3
(Ph), 128.3 (Ph), 138.0 (Ph), 138.5 (Ph); HRMS (ESI) Calcd for
(C24H31O5S) [MþH]þ: 431.1892; found 431.1874.
2.32 (m, 1H, H-4b), 2.33 (s, 3H, CH3COS), 3.38 (s, 3H, OCH3), 3.53 (m,
2H, CH2OCH3),3.64 (mAB, 2H, BnOCH2), 3.68 (m, 2H, OCH2CH2), 3.99
(d, J¼5.5 Hz, 1H, H-1), 4.02 (t, J¼5.8 Hz, 1H, H-3), 4.23 (dt, J¼8.3,
5.2 Hz, 1H, H-5), 4.53 (mAB, 2H, PhCH2O), 4.54 (d, J¼12.1 Hz, 1H,
PhCHaHO), 4.59 (d, J¼12.1 Hz, 1H, PhCHbHO), 4.71 (d, J¼7.1 Hz, 1H,
OCHaHO), 4.75 (d, J¼7.1 Hz,1H, OCHbHO), 7.27–7.34 (m,10H, aromatic
3.1.15. (1R,2S,4S,5S)-4-(Benzyloxy)-5-[(benzyloxy)methyl]-6-thiabi-
cyclo[3.1.0]hexan-2-ol (38). Method A. A solution of 37 (146 mg,
0.34 mmol) in tert-butanol (4 mL) was treated with p-toluene-
sulfonic acid (100 mg, 0.57 mmol) and the mixture was refluxed for
8 h. The solvent was evaporated and the residue was partitioned
between an aqueous saturated solution of sodium bicarbonate
(10 mL) and methylene chloride (10 mL). The aqueous layer was
extracted with methylene chloride (2ꢃ10 mL), and the combined
organic phases were dried (MgSO4), and the solvent was evaporated.
The residue was purified by column chromatography (silica gel)
eluting with a mixture of hexane–EtOAc (19:1) to give 97 mg (83%
yield) of compound 38 as a colorless oil. Method B. Compound 39
(21 mg, 0.047 mmol) was treated with methanolic ammonia (5 mL,
saturated at ꢁ78 ꢀC) and stirred in a sealed tube at 40 ꢀC for 15 h. The
solvent was evaporated and the residue was purified by column
chromatography (silica gel) eluting with hexane–EtOAc (19:1) to give
15 mg (89% yield) of 38 as a colorless oil: Rf 0.50 (hexane–EtOAc, 3:2);
protons); 13C NMR (125.77 MHz, CDCl3)
d 30.2 (CH3COS), 36.1 (C-4),
55.1 (C-1), 59.0 (OCH3), 67.0 (CH2OCH3), 70.3 (BnOCH2), 71.4
(PhCH2O), 71.7 (OCH2CH2), 73.6 (PhCH2O), 80.7 (C-5), 82.6 (C-2), 83.6
(C-3), 94.7 (OCH2O),127.4 (Ph),127.5 (Ph),127.6 (Ph),127.6 (Ph),128.3
(Ph), 128.3 (Ph), 137.9 (Ph), 138.3 (Ph), 196.2 (CH3C(O)S); HRMS (ESI)
Calcd for (C26H34O7SNa) [MþNa]þ: 513.1923; found 513.1896.
3.1.13. S-(1R,2R,3S,5S)-5-((2-Methoxyethoxy)methoxy)-3-(benzyl-
oxy)-2-((benzyloxy)methyl)-2-methanesulfonyloxycyclopentyl etha-
nethioate (36). To a solution of compound 35 (795 mg, 1.62 mmol)
in anhydrous pyridine (15 mL) in the presence of 4-N,N-dimethy-
laminopyridine (99 mg, 0.8 mmol) cooled at 0 ꢀC was added mesyl
chloride (3.8 mL, 48.7 mmol) dropwise. The reaction mixture was
stirred at room temperature for 24 h. Then, methylene chloride
(30 mL) was added and the mixture was washed with an aqueous
1.0 N solution of hydrochloric acid (3ꢃ20 mL) and water
(3ꢃ20 mL). The organic phase was dried (MgSO4), and the solvent
was evaporated. The residue was purified by column chromatog-
raphy (silica gel) employing a mixture of hexane–EtOAc (3:1) as
1H NMR (500.13 MHz, CDCl3)
d 1.92 (m, 2H, H-3), 3.09 (s, 1H, H-1),
3.44 (d, J¼10.8 Hz, 1H, BnOCHaH), 4.17 (d, J¼10.8 Hz, 1H, BnOCHbH),
4.38 (distorted d, J¼3.8 Hz, 1H, H-2), 4.49 (d, J¼11.9 Hz, 1H,
PhCHaHO), 4.56 (d, J¼12.0 Hz, 1H, PhCH0aHO), 4.59 (d, J¼11.6 Hz, 1H,
PhCHbHO), 4.63 (d, J¼12.1 Hz,1H, PhCH0bHO), 4.72 (t, J¼7.9 Hz,1H, H-
4), 7.27–7.35 (m, 10H, aromatic protons); 13C NMR (125.77 MHz,
eluent to afford 448 mg (48% yield) of pure compound 36 as a yel-
23
low pale oil: Rf 0.43 (hexane–EtOAc, 1:1); [
a
]
D
þ15.8 (c 1.0, CHCl3);
1H NMR (500.13 MHz, CDCl3)
d
2.12 (ddd, J¼14.0, 6.6, 5.2 Hz, 1H, H-
4a), 2.32 (m, 1H, H-4b), 2.33 (s, 3H, CH3C(O)S), 3.04 (s, 3H, CH3SO2),
3.37 (s, 3H, OCH3), 3.52 (distorted t, J¼4.5 Hz, 2H, CH2OCH3), 3.66
(dd, J¼11.2, 4.3 Hz, 1H,,BnOCHaH), 3.70 (dd, J¼11.2, 4.8 Hz, 1H,
BnOCHbHO), 3.96 (d, J¼10.1 Hz, 1H, PhCHaHO), 4.17 (d, J¼10.1 Hz,
1H, PhCHbHO), 4.26 (dt, J¼8.3, 4.9 Hz, 1H, H-5), 4.53–4.58 (m, 6H,
PhCH2O, H-1, H-3), 4.59 (d, J¼5.0 Hz, 1H, H-5), 4.68 (d, J¼7.1 Hz, 1H,
OCHaHO), 4.73 (d, J¼7.0 Hz, 1H, OCHbHO), 7.26–7.35 (m, 10H, aro-
CDCl3) d 36.1 (C-3), 47.4 (C-1), 55.3 (C-5), 71.4 (BnOCH2), 72.3
(PhCH2O), 72.4 (C-2), 73.0 (PhCH2O), 76.9 (C-4),127.7 (Ph),127.8 (Ph),
127.8 (Ph), 128.4 (Ph), 128.4 (Ph), 137.8 (Ph), 138.4 (Ph); HRMS (ESI)
Calcd for (C20H23O3S) [MþH]þ: 343.1368; found 343.1357.
3.1.16. (1R,2S,4S,5S)-4-(Benzyloxy)-5-((benzyloxy)methyl)-6-thiabi-
cyclo[3.1.0]hexan-2-yl benzoate (39). To a solution of benzoic acid
matic protons); 13C NMR (125.77 MHz, CDCl3)
d
30.2 (CH3COS), 36.2
(56 mg, 0.46 mmol) and diethyl azodicarboxylate (90
mL, 0.57 mmol)
(C-4), 40.6 (CH3SO2), 52.7 (C-1), 59.0 (OCH3), 67.1 (CH2OCH3), 67.6
in anhydrous tetrahydrofuran (1 mL) was added triphenylphosphine