1.
Potassium t-butoxide was purchased from Acros and used under a stream of N2.
2.
Et2O and THF were purchased from Fisher and dried by passage through an activated alumina column under N2.
3.
The reaction was successfully performed at temperatures ranging from −30°C to −50°C.
4.
(1R)-(+)-Camphor 98%, was purchased from Aldrich Chemical. The optical purity of (1R)-(+)-Camphor varies with the natural source. For analysis of the optical purity of commercial (+)- and (−)-camphor see: Armstrong, D. W.; Lee, J. T.; Chang, L. W. Tetrahedron: Asymmetry 1998, 9, 2043.
5.
Isoamyl nitrite was purchased form Aldrich Chemical Company, Inc. Because of the appalling odor of the reagent, it was used without prior distillation.
6.
Anti-(1S)-(−)-camphorquinone 3-oxime 1H NMR pdf (500 MHz, CDCl3) δ: 9.70-8.80 (br, 1 H, N-OH), 3.25 (d, J = 4.3, 1 H), 2.08-2.00 (m,1H), 1.83-1.74 (m, 1H), 1.62-1.52 (m, 2H), 1.00 (s, 3H), 1.03 (s, 3 H), 0.89 (s, 3H) ppm; 13C {1H} NMR (125 MHz, CDCl3) δ: 204.5, 160.1, 58.8, 47.1, 45.3, 31.1, 24.2, 21.1, 18.0, 9.3, 18.0 ppm. Syn-(1S)-(−)-camphorquinone 3-oxime 1H NMR pdf (500 MHz, CDCl3) δ: 9.70-8.80 (br, 1 H, N-OH), 2.70 (d, J = 4.2, 1 H), 2.14-2.08 (m, 1 H), 1.83-1.74 (m, 1 H), 1.66-1.55 (m, 2 H), 1.03 (s, 3 H), 1.01 (s, 3 H), 0.93 (s, 3 H) ppm; 13C {1H} NMR (125 MHz, CDCl3) δ: 205.3, 156.6, 60.0, 50.0, 47.4, 30.4, 25.4, 21.0, 18.4, 8.8 ppm.3,4a
7.
1.0 M LiAlH4 in THF was purchased from Aldrich. The yields and diastereoselectivity were much higher when homogeneous solutions of LiAlH4 were used instead of the powder form.
8.
H2 gas evolution was vigorous at the beginning of the addition.
9.
Addition of the initial 3.8 mL of water is accompanied by vigorous generation of H2 and is very exothermic.
10.
The best product recovery was accomplished when the filter cake was washed with THF. For spectral properties see reference4b.
11.
Bis(2-bromoethyl) ether (technical grade, 90% purity) was purchased from Aldrich. Reagent grade DMSO was purchased from Fisher. (Note revised 3/2017).
12.
~200 g of silica, 10% to 15% EtOAc in hexanes. TLC in 20% EtOAc in hexanes; Rf 0.25; Stained brown in I2 Chamber.
13.
Recrystallization is also possible from hexanes 4 mL/g at −30°C.5
14.
Characterization data for (2S)-(−)-exo-(morpholino)isoborneol: [α]20D = −6.9 (c = 1.0, MeOH); mp = 65-66°C (hexane); 1H NMR pdf (400 MHz, C6D6) δ: 3.91 (s, 1 H), 3.43 (d, 1 H, J = 7.1 Hz), 3.40 (bs, 4 H), 2.30 (bs, 2 H), 2.10 (bs, 2 H), 2.07 (d, 1 H, J = 7.1 Hz), 1.66 (d, 1 H, J = 4.7 Hz), 1.51 (tt, 1 H, J = 12.0, 4.6 Hz), 1.35 (td, 1 H, J = 12.2, 3.6), 1.13 (s, 3 H), 1.02 (s, 3 H), 0.92-0.82 (m, 1 H), 0.77-0.70 (m, 1 H), 0.68 (s, 3 H); 13C {1H} NMR (76 MHz, C6D6, d1 = 5 sec) δ 79.6, 74.0, 67.4, 50.1, 47.2, 46.0, 33.2, 28.6, 22.8, 21.7, 12.4; IR (KBr) 3460, 3367, 1478, 1448, 1396, 1360, 1284, 1261, 1202, and 1200 cm−1; EIMS m/z 239 (M+, 13), 154 (100); HRMS (EI) m/z calcd for C14H25NO3: 239.1885, found 239.1889. Enantiomeric excess was determined as followed: To a screw cap vial (1 dram) charged with (−)-MIB (24 mg, 0.1 mmol) was added dichloromethane (1 mL), followed by Et3N (17 µL, 0.12 mmol), and DMAP (~2 mg). p-Bromobenzoyl chloride (22 mg, 0.1 mmol) was added to the clear solution and stirred for 10 min. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (5% ethyl acetate in hexanes). HPLC analysis of the resultant p-bromobenzyl ester established the enantiomeric excess as 96.0% ee (Chiralcel OD column, flow 1 mL/min, 254 nm, 2% isopropanol in hexanes; minor isomer 4.6 min, and major isomer 5.3 min).