Organic & Biomolecular Chemistry
Paper
the hydrophobic pocket (Trp312, Tyr313, Phe316, Val343 and
(5R,7aS)-5-Dodecyl-1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-
1
Lys346); (d) α-1-C-tridecyl-DAB improved the thermostability of one (2i). 60% yield; H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t,
β-glucocerebrosidase in vitro and displayed comparable J = 6.8 Hz,), 1.26–1.56 (22H, m), 4.22 (1H, dd, J = 5.8, 8.2 Hz),
enhancement of activity at a concentration 10 times lower than 4.53 (1H, brs), 4.60 (1H, t, J = 8.7 Hz), 4.74 (1H, brs), 5.83–5.85
isofagomine. α-1-C-Tridecyl-DAB therefore represents a new (1H, m), 6.03 (1H, ddd, J = 2.4, 2.4, 6.3 Hz). 13C-NMR
class of potential pharmacological chaperones with potential (100 MHz, CDCl3) δ: 14.08, 22.64, 26.19, 29.31, 29.41, 29.49,
for the treatment of Gaucher disease.
29.54, 29.60, 29.62, 31.87, 34.38, 63.84, 67.47, 68.71, 127.96,
135.27, 162.97. IR (neat) cm−1: 1743, 2851, 2917. EI-MS (m/z):
293 (M+). HRMS Calcd for C18H31NO2: 293.2355, Found:
293.2354. [α]2D6 = −124.8 (c 0.15, CHCl3).
Experimental section
General experimental procedures
(5R,7aS)-5-Tridecyl-1,7a-dihydropyrrolo[1,2-c]oxazol-3(5H)-
one (2j). 60% yield; H-NMR (400 MHz, CDCl3) δ: 0.88 (3H, t,
1
Infrared (IR) spectra were recorded on a Perkin-Elmer 1600
series FT-IR spectrometer. Mass spectra (MS) were recorded on
a JEOL JMN-DX 303/JMA-DA 5000 spectrometer. Microanalyses
were performed on a Perkin-Elmer CHN 2400 Elemental Analy-
zer. Optical rotations were measured with a JASCO DIP-360 or
JASCO P-1020 digital polarimeter. Proton nuclear magnetic res-
onance (1H NMR) spectra were recorded on JEOL JNM-AL 400
(400 MHz) spectrometer, using tetramethylsilane as an
internal standard. The following abbreviations are used: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad. Column chromatography was carried out on Merck
Silica gel 60 (230–400 mesh) or KANTO Silica Gel 60N
(40–50 mm) for flash chromatography.
J = 6.3 Hz), 1.26–1.54 (24H, m), 4.22 (1H, dd, J = 5.3, 8.7 Hz),
4.53 (1H, brs), 4.60 (1H, t, J = 8.7 Hz), 4.74 (1H, m), 5.85(1H,
dd, J = 1.4, 5.8 Hz), 6.03 (1H, ddd, J = 2.4, 2.4, 6.2 Hz).
13C-NMR (100 MHz, CDCl3) δ: 14.08, 22.64, 26.19, 29.32, 29.41,
29.50, 29.54, 29.60, 29.62, 29.64, 31.87, 34.39, 63.84, 67.47,
68.71, 127.97, 135.27, 162.98. IR (neat) cm−1: 1745, 2849, 2917.
EI-MS (m/z): 307 (M+). HRMS Calcd for C19H33NO2: 307.2511,
Found: 307.2519, [α]1D7 = −107.9 (c 0.52, CHCl3).
Typical procedure for epoxidation
To a vial with alkene 2 (1.18 mmol) were added 11 mL of
CH3CN and 7.6 mL of 4 × 10−4 M ethylenediaminetetraacetic
acid in H2O. The solution was cooled to 0 °C, and 1,1,1-tri-
fluoroacetone (1.33 g, 11.9 mmol) was added. A mixture of
solid Oxone™ (3.63 g, 4.36 mmol) and NaHCO3 (743 mg,
8.85 mmol) was added in four portions over 45 min. The reac-
tion was stirred for 2 h at 0 °C, then diluted with 5 mL of H2O,
and extracted with CH2Cl2 (3 × 25 mL). The organic layers were
combined and dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo furnished the crude product, which was
purified by column chromatography (silica gel eluting with
hexane/EtOAc) to provide epoxides 3a–j. Compounds 3a–h
were identical in 1H-NMR with ent-3a–h which were reported
previously.26
(5S,7aS)-5-(Iodomethyl)-1,7a-dihydropyrrolo[1,2-c]oxazol-3-
(5H)-one (1). The iodide 1 was prepared according to reported
procedure.25,26 [α]D24 = −131.7 (c 1.04, CHCl3). Lit. ent-1: [α]D23
+141.6 (c 1.0, CHCl3).25
=
Typical procedure for the preparation of alkylzinc bromide
Iodine chips (127 mg, 0.50 mmol) were added to a suspension
of Zn powder (981 mg, 15.0 mmol) in N,N-dimethylacetamide
(10 mL) at room temperature. After stirring for 10 min, the
resulting mixture changed from a dark-brown suspension to a
colorless suspension. Alkylbromide (10 mmol) was added by
syringe, and the reaction mixture was stirred at 80 °C for 3 h.
The concentration in N,N-dimethylacetamide was ∼0.75 M.
(1aS,1bR,6R,6aR)-6-Dodecyltetrahydrooxireno[2′,3′:3,4]pyrrolo-
[1,2-c]oxazol-4(1aH)-one (3i). 80% yield; 1H-NMR (400 MHz,
CDCl3) δ: 0.88 (3H, t, J = 6.8 Hz), 1.26–1.51 (22H, m), 3.55
Typical procedure for Negishi coupling
Yellow bis(1,5-cyclooctadiene)nickel(0) (83.1 mg, 0.302 mmol, (1H, d, J = 2.9 Hz), 3.61 (1H, d, J = 2.9 Hz), 3.98 (1H, dd, J = 3.7,
16 mol%) and (R,R)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine 8.7 Hz), 4.04 (1H, dd, J = 4.8, 9.2 Hz), 4.47 (1H, t, J = 4.3 Hz),
(182 mg, 0.604 mmol, 32 mol%) were added to N,N-dimethyl- 4.55 (1H, dd, J = 9.2, 17.9 Hz). 13C-NMR (100 MHz, CDCl3) δ:
acetamide (12.0 mL) under an argon atmosphere, and the 14.08, 22.64, 26.06, 29.29, 29.31, 29.41, 29.50, 29.59, 29.61,
resulting mixture was stirred for 30 min at room temperature. 30.01, 31.87, 55.26, 57.17, 58.70, 60.45, 64.63, 162.54. IR (neat)
The resulting deep-blue solution was added to a solution of cm−1: 1747, 2850, 2919. EI-MS (m/z): 309 (M+). HRMS Calcd for
the alkylzinc bromide (in N,N-dimethylacetamide, 8.7 mL, C18H31NO3: 309.2304, Found: 309.2309, [α]2D5 = −34.3 (c 0.35,
6.05 mmol) and 1 (500 mg, 1.89 mmol). After being stirred for CHCl3).
20 h, the reaction was quenched with iodine chips (440 mg).
(1aS,1bR,6R,6aR)-6-Tridecyltetrahydrooxireno[2′,3′:3,4]pyrrolo-
After being stirred for 10 min, the dark-brown mixture was [1,2-c]oxazol-4(1aH)-one (3j). 80% yield; 1H-NMR (400 MHz,
passed through a short pad of silica gel (eluting with AcOEt/ CDCl3) δ: 0.88 (3H, t, J = 7.2 Hz), 1.26–1.55 (24H, m), 3.55–3.61
hexane = 1/1) (to remove N,N-dimethylacetamide, inorganic (2H, m), 3.97–4.02 (2H, m), 4.48–4.53 (2H, m), 13C-NMR
salts, and iodine). The filtrate was then concentrated, and the (100 MHz, CDCl3) δ: 14.10, 22.67, 26.08, 29.32, 29.33, 29.43,
residue was purified by flash chromatography (silica gel 29.51, 29.61, 29.66, 30.04, 31.89, 55.26, 57.19, 58.74, 60.46,
eluting with hexane/EtOAc) to provide coupled products 2a–j. 64.64, 162.54. IR (neat) cm−1: 1757, 2850, 2918. EI-MS (m/z):
Compounds 2a–h were identical in 1H-NMR with ent-2a–h 323 (M+). HRMS Calcd for C19H33NO3: 323.2460, Found:
which were reported previously.26
323.2449, [α]1D9 = −26.2 (c 0.21, CHCl3).
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