Three Novel Scaffolds for Potential Glycosidase Inhibitors
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1206 (m), 1112 (s), 1028 (w), 999 (w), 824 (m), 739 (s), 701 (s), 612
(dd, J = 12.5, 6.0 Hz, 1 H, 1-Ha, 20a), 3.38 (dd, J = 11.5, 6.9 Hz,
(m), 505 (s), 490 (w) cm–1. C42H50O5Si (674.94): calcd. C 76.09, H 1 H, 1-Hb, 20b), 3.53 (dd, J = 12.6, 3.0 Hz, 1 H, 1-Hb, 20a), 3.64
7.60; found C 76.19, H 7.93.
(dd, J = 6.1, 2.9 Hz, 1 H, 3-H, 20b), 3.67–3.74 (m, 3 H, 3-H, 20a,
7-Ha), 3.79 (t, J = 6.4 Hz, 1 H, 4-H, 20b), 3.83 (dd, J = 8.0, 3.7 Hz,
1 H, 4-H, 20a), 3.87 (dd, J = 11.0, 3.0 Hz, 1 H, 7-Hb, 20a), 3.89
(dd, J = 13.4, 2.6 Hz, 1 H, 7-Hb, 20b), 3.94–4.00 (m, 2 H, 2-H),
4.10–4.16 (m, 3 H, 5-H, 20b, 6-H), 4.25 (dd, J = 8.0, 6.9 Hz, 1 H,
5-H, 20a), 4.55 (d, J = 11.1 Hz, 2 H, PhCH2), 4.61 (d, J = 11.2 Hz,
2 H, PhCH2), 4.72 (d, J = 11.5 Hz, 1 H, PhCH2, 20a), 4.74 (d, J
= 11.9 Hz, 1 H, PhCH2, 20b), 4.76 (d, J = 11.2 Hz, 1 H, PhCH2,
20a), 4.84 (d, J = 11.2 Hz, 1 H, PhCH2, 20b), 7.20–7.42 (m, 32 H,
CHar), 7.64–7.71 (m, 8 H, CHar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.4 [2 C, C(CH3)3], 23.47 (2 C), 23.55, 23.6
(CqCH2CH2), 26.9 [6 C, C(CH3)3], 37.3, 37.4 (2 C), 37.5
(CqCH2CH2), 53.6 (C-1, 20b), 54.1 (C-1, 20a), 64.6 (2 C, C-7), 70.5
(2C, C-2), 74.4, 74.5 (PhCH2, 20a), 74.7, 75.0 (PhCH2, 20b), 75.2
(C-5, 20a), 76.2 (C-5, 20b), 79.8 (C-3, 20a), 80.0 (C-4, 20a), 80.2
(C-4, 20b), 80.4 (C-3, 20b), 80.5 (C-6, 20b), 80.7 (C-6, 20a), 119.3
(CqCH2, 20a), 119.5 (CqCH2, 20b), 127.7, 127.95, 128.01, 128.1,
128.16, 128.22, 128.3, 128.55, 128.60, 129.7 (32 C, CHar), 133.4 (2
C), 133.5 (2 C, Cq,ar), 135.76, 135.82 (8 C, CHar), 137.67, 137.74,
(2RS,3S,4R,5S,6R)-3,4-Dibenzyloxy-7-(tert-butyldiphenylsilyloxy)-
5,6-(cyclopentylidenedioxy)-1,2-epoxyheptane (19): Alkene 18
(1.44 g, 2.17 mmol) was dissolved in CH2Cl2 (20 mL) and treated
with mCPBA (70% in H2O, 588 mg, 2.39 mmol). The mixture was
stirred for 18 h, then more mCPBA (70 % in H2O, 1.34 g,
5.44 mmol) was added, and it was stirred for further 42 h. The reac-
tion was quenched by addition of semisatd. Na2S2O3 (50 mL) with
subsequent stirring for 5 min. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3ϫ30 mL). The com-
bined organic layers were washed with satd. NaHCO3 (20 mL) and
H2O (20 mL), dried with MgSO4 and concentrated in vacuo. The
crude product was purified by flash column chromatography (40 g
silica, n-pentane/MTBE, 6:1) to provide the epoxide 19 (1.28 g,
1.89 mmol, 87 %) as a 3:2 mixture of epimers in the form of a
colourless oil. Rf = 0.52 (n-hexane/MTBE, 3:1); [α]2D0 = +14.7 (c =
1
3.68, in CHCl3). H NMR (300 MHz, CDCl3, TMS): δ = 1.04 [s,
18 H, C(CH3)3], 1.52–1.89 [m, 16 H, (CH2)4], 2.50 (dd, J = 4.4,
2.2 Hz, 1 H, 1-Ha, 19b), 2.58 (dd, J = 5.0, 2.3 Hz, 1 H, 1-Ha, 19a),
2.65 (t, J = 4.0 Hz, 1 H, 1-Hb, 19b), 2.78 (dd, J = 4.6, 4.2 Hz, 1 H,
1-Hb, 19a), 3.15 (m, 1 H, 2-H, 19a), 3.19–3.30 (m, 2 H, 2-H, 3-H,
19b), 3.44 (dd, J = 6.2, 2.3 Hz, 1 H, 3-H, 19a), 3.61–3.74 (m, 4 H,
4-H, 7-Ha), 3.80–3.90 (m, 2 H, 7-Hb), 4.04 (m, 1 H, 6-H, 19a),
4.11–4.25 (m, 3 H, 5-H, 19a, 5-H, 6-H, 19b), 4.55–4.71 (m, 6 H,
PhCH2), 4.76 (d, J = 11.5 Hz, 1 H, PhCH2, 19a), 4.84 (d, J =
12.0 Hz, PhCH2, 1 H, 19b), 7.19–7.44 (m, 32 H, CHar), 7.64–7.73
(m, 8 H, CHar) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.4 [2 C,
C(CH3)3], 23.5 (2 C), 23.7 (2 C, CqCH2CH2), 26.9 [6 C, C(CH3)3],
37.5 (4 C, CqCH2CH2), 43.4 (C-1, 19b), 47.4 (C-1, 19a), 51.0 (C-2,
19a), 53.4 (C-2, 19b), 64.9 (C-7, 19b), 65.1 (C-7, 19a), 72.6 (PhCH2,
19b), 73.5 (PhCH2, 19a), 74.5 (PhCH2, 19b), 74.6 (C-5, 19a), 75.0
(PhCH2, 19a), 75.7 (C-5, 19b), 78.6 (C-3, 19a), 80.3 (C-6, 19b), 80.7
(C-6, 19a), 81.2 (C-4, 19a), 81.4 (C-4, 19b), 81.9 (C-3, 19b), 119.1
(2 C, CqCH2), 127.6, 127.67, 127.71, 127.8, 127.9, 128.0, 128.07,
128.15, 128.3, 128.4, 128.50, 128.55, 129.65, 129.71 (32 C, CHar),
133.5, 133.6 (2 C), 133.7 (Cq,ar), 135.8, 135.86, 135.91 (8 C, CHar),
137.8, 137.9 (Cq,ar) ppm. IR (film): ν = 3454 (br. m), 3069 (m),
˜
3031 (m), 2931 (s), 2858 (s), 2103 (s), 1589 (w), 1497 (w), 1472 (m),
1454 (s), 1428 (s), 1391 (w), 1360 (w), 1335 (s), 1281 (br. m), 1209
(m), 1113 (s), 1028 (w), 824 (m), 738 (s), 701 (s), 613 (m), 506
(s) cm–1. HRMS (ESI): m/z calcd. for C42H51N3NaO6Si: 744.3439;
found: 744.3446 [M + Na]+. C42H51N3O6Si (721.96): calcd. C
69.87, H 7.12, N 5.82; found C 69.99, H 7.11, N 5.98.
(3R,4S,5S,6R)-1-Azido-3,4-dibenzyloxy-7-(tert-butyldiphenylsilyl-
oxy)-5,6-(cyclopentylidenedioxy)heptan-2-one (21): A solution of
oxalyl chloride (950 μL, 10.9 mmol) in CH2Cl2 (11 mL) was cooled
to –60 °C and DMSO (1.55 mL, 21.8 mmol) in CH2Cl2 (2.5 mL)
was added dropwise, and the mixture was stirred for 5 min. Then
alcohol 20 (3.15 g, 4.36 mmol) in CH2Cl2 (6.5 mL) was added
slowly, and after 10 min the temperature was raised to –20 °C. The
mixture was stirred for 1 h, then Et3N (6.65 mL, 48.0 mmol) was
added dropwise at –60 °C with subsequent warming to room temp.
and further stirring for 10 min. Workup was performed by adding
H2O (50 mL). The aqueous layer was extracted with CH2Cl2
(2ϫ50 mL), and the combined organic layers were washed with
H2O (50 mL), dried with MgSO4 and concentrated in vacuo. Flash
column chromatography (250 g silica, n-pentane/MTBE, 7:1)
yielded the heptanone 21 (2.62 g, 3.64 mmol, 83%) as colourless
oil. Rf = 0.18 (n-hexane/MTBE, 9:1); [α]2D0 = +42.0 (c = 2.78, in
CHCl3). 1H NMR (300 MHz, CDCl3, TMS): δ = 1.04 [s, 9 H,
C(CH3)3], 1.55–1.91 [m, 8 H, (CH2)4], 3.68 (dd, J = 11.1, 5.0 Hz,
1 H, 7-Ha), 3.85 (dd, J = 11.0, 2.4 Hz, 1 H, 7-Hb), 3.95 (dd, J =
8.3, 2.7 Hz, 1 H, 4-H), 3.99 (d, J = 19.5 Hz, 1 H, 1-Ha), 4.04–4.19
(m, 3 H, 1-Hb, 5-H, 6-H), 4.24 (d, J = 2.7 Hz, 1 H, 3-H), 4.45 (s,
2 H, PhCH2), 4.55 (d, J = 11.5 Hz, 1 H, PhCH2), 4.69 (d, J =
11.5 Hz, 1 H, PhCH2), 7.10–7.44 (m, 16 H, CHar), 7.68 (m, 4 H,
CHar) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.4 [C(CH3)3], 23.5
(2 C, CqCH2CH2), 26.9 [3 C, C(CH3)3], 37.4, 37.5 (CqCH2CH2),
57.2 (C-1), 64.7 (C-7), 74.6 (C-5), 74.7, 75.0 (PhCH2), 80.8 (C-6),
82.3 (C-4), 84.8 (C-3), 119.6 (CqCH2), 127.70 (2 C), 127.74 (2 C),
128.18, 128.25 (2 C), 128.5 (3 C), 128.6 (2 C), 128.8 (2 C), 129.7 (2
C, CHar), 133.4, 133.5 (Cq,ar), 135.7 (2 C), 135.8 (2 C, CHar), 136.7,
137.76, 137.83, 138.36, 138.39 (Cq,ar) ppm. IR (film): ν = 3068 (m),
˜
3031 (m), 2931 (s), 2858 (s), 1589 (w), 1497 (w), 1472 (w), 1454
(m), 1428 (m), 1390 (w), 1335 (m), 1207 (m), 1112 (s), 1028 (m),
980 (m), 823 (m), 740 (s), 701 (s), 612 (m), 505 (s), 491 (m) cm–1.
HRMS (ESI): m/z calcd. for C42H50NaO6Si: 701.3269; found:
701.3274 [M + Na]+. C42H50O6Si (678.93): calcd. C 74.30, H 7.42;
found C 74.24, H 7.31.
(2RS,3S,4R,5S,6R)-1-Azido-3,4-dibenzyloxy-7-(tert-butyldiphenyl-
silyloxy)-5,6-(cyclopentylidenedioxy)heptan-2-ol (20): A mixture of
the epoxide 19 (4.15 g, 6.11 mmol), NH4Cl (409 mg, 7.64 mmol)
and NaN3 (1.65 g, 25.4 mmol) in EtOH (65 mL) was heated to re-
flux for 45 h. Then the solvent was evaporated, and the residue was
redissolved in MTBE (50 mL) and H2O (50 mL). The aqueous
phase was extracted with MTBE (2ϫ30 mL), and the combined
organic layers were washed with H2O (25 mL) and brine (25 mL),
dried with MgSO4 and concentrated in vacuo. The residue was sep-
arated by flash column chromatography (130 g silica, n-pentane/
MTBE, 5:1) to yield both the desired alcohol 20 (3.84 g,
5.32 mmol, 87%) as colourless oil and recovered starting material
19 (455 mg, 670 μmol, 11%). The yield of alcohol 20 with respect
to 89 % conversion was 98 %. Rf = 0.30 (n-hexane/MTBE, 3:1);
[α]2D0 = –6.8 (c = 2.44, in CHCl3). 1H NMR (500 MHz, CDCl3,
137.0 (Cq,ar), 206.7 (C-2) ppm. IR (film): ν = 3442 (br. w), 3069
˜
(w), 3032 (w), 2958 (s), 2932 (s), 2858 (s), 2106 (s), 1730 (s), 1589
(w), 1497 (w), 1472 (m), 1455 (m), 1428 (m), 1391 (w), 1335 (s),
TMS): δ = 1.04 [s, 9 H, C(CH3)3, 20a], 1.06 [s, 9 H, C(CH3)3, 20b], 1280 (m), 1206 (m), 1113 (s), 910 (m), 824 (m), 738 (s), 702 (s), 613
1.58–1.90 [m, 16 H, (CH2)4], 2.66 (br. s, 1 H, OH, 20b), 2.81 (br. s,
(m), 505 (s) cm–1. HRMS (ESI): m/z calcd. for C42H49N3NaO6Si:
1 H, OH, 20a), 3.18 (dd, J = 12.4, 5.3 Hz, 1 H, 1-Ha, 20b), 3.35 742.3283; found: 742.3283 [M + Na]+.
Eur. J. Org. Chem. 2007, 4408–4430
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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