A. Michaud et al. / Tetrahedron: Asymmetry 22 (2011) 819–822
821
recorded on an Agilent MSTOF-6210 (electrospray or chemical ion-
isation) spectrometer. Flash column chromatography was carried
out using 40–63 m (230–400 mesh) silica gel. CAL-B (C. antarctica
3.5. (1R,2R,3S,4S)-2-(Acetoxymethyl)-3-(tosyloxymethyl)-7-
azabicyclo[2.2.1]heptane hydrochloride 5
l
lipase B (Chirazyme L2) was obtained from Boehringer Mannheim.
CCL (C. cylindracea lipase), CRL (C. rugosa lipase), and BCL (B. cepacia
lipase) were from Fluka-Sigma–Aldrich. Lipase G (from penicillium
sp.), Lipase D (from Rhizopus sp.), Mucor sp. lipase, and ANL (A. niger
lipase) were from Amano International Enzyme.
To a solution of monoester 4 (126 mg, 0.42 mmol) in anhydrous
CH2Cl2 (5 mL) was added triethylamine (85 mg, 0.84 mmol) fol-
lowed by para-toluenesulfonyl chloride (88 mg, 0.46 mmol). The
solution was stirred at room temperature and the reaction was
monitored by TLC (EtOAc/hexane, 9:1). When all the starting mate-
rial was consumed, the reaction mixture was diluted with Et2O
(100 mL), washed with saturated aqueous NaHCO3 (4 ꢁ 100 mL)
and brine (100 mL). The organic phase was dried over MgSO4 and
concentrated. Flash chromatography (EtOAc/hexane, 7:3) failed
to provide the pure tosylate and the crude product was carried into
the next step without further purification. The intermediate was
treated with HCl in dioxane (4.0 M, 3 mL) for 2 h at room temper-
ature. The volatiles were evaporated and the crude product was
recrystallized (minimum MeOH/EtOAc: 1:1 then hexane at
ꢀ20 °C) for X-ray diffraction analysis. Mp 164–169 (dec.);
3.2. 2,3-Di-endo(hydroxymethyl)-7-tert-butoxycarbonyl-7-
azabicyclo[2.2.1]heptane meso-2
A solution of LiAlH4 (350 mg, 9.22 mmol) in anhydrous THF
(30 mL) was cooled to 0 °C under an argon atmosphere. A solution
of diester 1 (1.38 g, 4.40 mmol) in anhydrous THF (30 mL) was
added dropwise over a period of 20 min. The reaction mixture
was stirred at room temperature for 18 h. The mixture was cooled
to 0 °C and the reaction was quenched by the careful, dropwise
addition of H2O (0.5 mL), 2.6 M NaOH (1.1 mL), and H2O (1.2 mL).
The mixture was stirred at room temperature until gas evolution
ceased. The bulk of THF was evaporated, water was added
(40 mL), and the aluminum salts were removed by filtration. The
aqueous phase was extracted with ethyl acetate (3 ꢁ 40 mL). The
organic layers were combined, dried over MgSO4, and evaporated.
Flash column chromatography (CH2Cl2/acetone, 1:1) afforded diol
2 (1.06 g, 94%) as a colorless oil which crystallized on standing.
½
a 2D0
ꢂ
¼ ꢀ1:3 (c 2.34, MeOH); IR (KBr) 3409, 2852, 1736, 1368,
1237, 1176, 818 cmꢀ1 1H NMR (400 MHz, CD3OD) d 1.82 (m,
;
4H), 1.88 (s, 3H), 2.44 (s, 3H), 2.75 (m, 2H), 4.10–4.27 (m, 6H),
7.44 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H); 13C NMR
(100 MHz, CD3OD) d 19.4, 20.4, 20.6, 20.7, 37.8, 38.2, 59.4, 61.4,
61.6, 65.8, 127.9, 130.1, 132.6, 145.8, 170.7; HRMS (ES) calcd for
C17H24NO5S (MH+): 354.1298. Found: 354.1371.
Mp 87–90 °C, IR (NaCl) 3420, 1694, 1359, 903 cmꢀ1
;
1H NMR
Acknowledgment
(400 MHz, CDCl3) d 1.43 (m, 2H), 1.46 (s, 9H), 1.61 (m, 2H), 2.35
(br s, 1H), 2.52 (m, 2H), 3.67 (m, 2H), 3.87 (m, 2H), 4.15 (m, 2H);
13C NMR (100 MHz, CDCl3) d 23.9, 28.5, 44.5, 59.2, 60.2, 80.3,
155.6; HRMS (CI, NH3) calcd for C13H24NO4 (MH+): 258.1705.
Found: 258.1712.
We acknowledge the financial support of this work by the Nat-
ural Sciences and Engineering Research Council of Canada (NSERC).
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155.3, 170.9; HRMS (CI, NH3) calcd for C17H28NO6 (MH+):
342.1916. Found: 342.1909.
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3.4. (1R,2R,3S,4S)-2-(Acetoxymethyl)-3-(hydroxymethyl)-7-
(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane 4
At first, C. antarctica lipase B (150 units) was added to a solution
of diol 2 (50.0 mg, 0.194 mmol) and vinyl acetate (1 mL, 0.934 g,
10.8 mmol) in diethyl ether (1 mL), and the mixture was stirred
at room temperature. The reaction course was monitored by TLC
(EtOAc) and stopped by filtration of the enzyme on Celite after
2 h. The volatiles were removed under pressure. Flash column
chromatography (ethyl acetate/hexane: 1:1) provided 4 (44.0 mg,
76%) as a colorless oil. ½a D20
ꢂ
¼ ꢀ8:4 (c 0.5, CHCl3); IR (NaCl) 3420,
1690, 1368, 1166, 911 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 1.45 (s,
9H), 1.65 (m, 4H), 2.05 (s, 3H), 2.12 (br s, 1H), 2.48 (m, 2H), 3.59
(m, 1H), 3.71 (m, 1H), 4.02 (m, 1H), 4.19 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 21.2, 23.2, 28.5, 40.4, 43.7, 59.3, 60.0, 62.0,
80.1, 155.6, 171.1; HRMS (CI, NH3) calcd for C15H26NO5 (MH+):
300.1811. Found: 300.1816.