Enantiopure Aminopyrans
FULL PAPER
were added and the layers were separated. The organic layer was succes-
sively washed with H2O, dried (MgSO4), and the solvent was removed in
vacuo. Purification by column chromatography (silica gel, hexane/EtOAc
4:1 ! 1:1) yielded 28 (250 mg, 79%) as colorless crystals. M.p. 64–658C;
[a]2D2 =+14.1 (c=1.43, CHCl3); 1H NMR (CDCl3, 500 MHz): d=0.05,
0.06 (2s, 3H each, SiMe2), 0.88 (s, 9H, tBu), 1.29, 1.47 (2s, 3H each,
Me), 1.51 (s, 9H, tBu), 2.43 (dd, J=1.6, 4.9 Hz, 1H, 5-H), 3.57 (dd, J=
6.5, 10.6 Hz, 1H, 4-CH2), 3.58 (dd, J=6.5, 10.6 Hz, 1H, 4-CH2), 4.15 (t,
J=6.5 Hz, 1H, 4-H), 4.15 (t, J=4.9 Hz, 1H, 8-H), 4.30 (dd, J=1.6,
4.9 Hz, 1H, 1-H), 4.60 (brs, 2H, CH2Ph), 7.25–7.38 ppm (m, 5H, Ph);
13C NMR (CDCl3, 500 MHz): d=ꢀ5.3, ꢀ5.1 (2q, SiMe2), 18.1 (s, tBu),
24.5, 29.0 (2q, Me), 25.9 (q, tBu), 28.0 (q, tBu), 53.3 (d, C-5), 55.0 (d, C-
1), 63.7 (t, 4-CH2), 68.1 (d, C-4), 71.8 (t, CH2Ph), 72.9 (d, C-2), 75.6 (d,
C-8), 83.1 (s, tBu), 127.5, 128.1, 128.6, 136.8 (3 d, s, Ph), 149.4 (s, NCO2),
M.p. 101–1038C; [a]D22 =+92.5 (c=1.00, CHCl3); 1H NMR (CDCl3,
500 MHz): d=1.31, 1.48 (2s, 3H each, Me), 1.60 (m, 1H, 5-H), 2.00 (d,
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J=2.6 Hz, 1H, OH), 2.39 (t, J=2.4 Hz, 1H, C CH), 2.69 (t, J=1.8 Hz,
1H, 1-H), 3.76 (dd, J=5.9, 9.1 Hz, 1H, 4-H), 3.86 (dd, J=6.5, 9.1 Hz,
ꢂ
1H, 4-H), 4.08 (dd, J=2.4, 15.8 Hz, 1H, CH2C CH), 4.13 (m, 3H, NCH2,
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8-CH2), 4.17 (dd, J=2.4, 15.8 Hz, 1H, CH2C CH), 4.31 (d, J=13.6 Hz,
1H, NCH2), 4.40 (dt, J=2.0, 6.4 Hz, 1H, 8-H), 4.67 (d, J=2.5 Hz, 1H, 9-
H), 7.25–7.37 ppm (m, 5H, Ph); 13C NMR (CDCl3, 125 MHz): d=26.5,
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29.5 (2q, Me), 42.6 (d, C-5), 57.5 (t, NCH2), 57.7 (d, C-1), 58.4 (t, CH2C
CH), 65.1 (d, C-9), 66.5 (t, 8-CH2), 67.3 (d, C-8), 70.8 (t, C-4), 73.2 (s, C-
ꢂ
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6), 74.4 (s, C CH), 79.8 (d, C CH), 127.3, 128.3, 128.5, 137.6 ppm (3d, s,
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Ph); IR (KBr): n˜ =3440 (O H), 3280 ( C-H), 3090–2870 (=C-H, C-H),
2120 cmꢀ1 (C C); HRMS (ESI-TOF): m/z: calcd for 332.1862; found
ꢂ
332.1867 [C19H25NO4+H]+; elemental analysis calcd (%) for C19H25NO4
ꢀ
170.9 ppm (s, NCO); IR (KBr): n˜ =3120–3030 (=C-H), 2960–2860 (C H),
(331.4): C 68.86, H 7.60, N 4.23; found C 68.36, H 7.62, N 4.21.
1790 cmꢀ1 (C=O); elemental analysis calcd (%) for C27H43NO6Si (505.3):
AHCTUNGTRENNUNG
C 64.12, H 8.57, N 2.77; found C 64.22, H 8.75, N 2.78.
AHCTUNGTRENNUNG
(3S,4S,5R,6S)-4-Benzyloxy-5-tert-butoxycarbonylamino-6-tert-butyldime-
thylsiloxymethyl-2,2-dimethyltetrahydropyran-3-carboxylic acid (29): To a
solution of g-lactam 28 (434 mg, 0.858 mmol) in THF/H2O 2:1 (9 mL)
was added LiOH (103 mg, 4.29 mmol). The resulting mixture was stirred
for 12 h. To the reaction mixture was added 0.1m HCl to adjust pH ~3.
The solution was extracted with EtOAc. The combined organic layers
were washed with H2O, dried with MgSO4 and concentrated to dryness
to yield 29 (392 mg, 85%) as colorless oil. [a]2D2 =ꢀ6.1 (c=0.45, CHCl3);
1H NMR (CDCl3, 500 MHz): d=0.06 (s, 6H, SiMe2), 0.89 (s, 9H, tBu),
1.26 (s, 9H, tBu), 1.31, 1.52 (2s, 3H each, Me), 2.30 (d, J=4.8 Hz, 1H, 3-
H), 3.51 (dd, J=7.3, 10.5 Hz, 1H, 6-CH2), 3.63 (dd, J=4.4, 10.5 Hz, 1H,
6-CH2), 3.70 (dd, J=2.3, 4.8 Hz, 1H, 5-H), 4.01 (dd, J=4.4, 7.3 Hz, 1H,
6-H), 4.21 (t, J=4.8 Hz, 1H, 4-H), 4.60, 4.69 (AB system, JAB =11.7 Hz,
2H, CH2Ph), 5.78 (brs, 1H, NH), 7.23–7.37 ppm (m, 5H, Ph); 13C NMR
(CDCl3, 125 MHz): d=ꢀ5.2 (q, SiMe2), 18.3 (s, tBu), 21.4 (q, tBu), 24.9
(q, tBu), 29.3, 29.7 (2q, Me), 50.8 (d, C-5), 52.5 (d, C-3), 63.5 (t, 6-CH2),
66.2 (d, C-6), 71.8 (s, C-2), 72.2 (t, CH2Ph), 77.2 (s, tBu), 77.8 (d, C-4),
127.6, 128.0, 128.6, 139.5 (3d, s, Ph), 157.7 (s, NCO2), 175.0 ppm (s,
(63 mL, 0.78 mmol) and Et3N (0.25 mL, 1.7 mmol) were added to a stirred
solution of bicyclic ketone 2 (100 mg, 0.343 mmol) in dry CH2Cl2 (5 mL).
After 4 h, the reaction mixture was diluted with dichloromethane and
washed excessively with sat. NaHCO3 solution. The crude product
(176 mg) was purified by column chromatography (silica gel, hexane/
EtOAc 1:1) to yield product 31 (129 mg, quant.) as colorless crystals.
M.p. 124–1268C; [a]D22 =+58.3 (c=0.60, CHCl3); 1H NMR (CDCl3,
500 MHz): d=1.20, 1.41 (2s, 3H each, Me), 2.28 (td, J=2.0, 4.0 Hz, 1H,
5-H), 2.94 (s, 3H, Ms), 3.05 (t, J=2.0 Hz, 1H, 1-H), 3.93 (d, J=13.1 Hz,
1H, NCH2), 4.17 (d, J=13.1 Hz, 1H, NCH2), 4.18 (ddd, J=2.0, 5.5,
6.4 Hz, 1H, 8-H), 4.35 (dd, J=5.5, 10.4 Hz, 1H, 8-CH2), 4.52 (dd, J=2.0,
12.4 Hz, 1H, 4-H), 4.53 (dd, J=6.4, 10.4 Hz, 1H, 8-CH2), 4.60 (dd, J=
4.0, 12.4 Hz, 1H, 4-H), 7.25–7.34 ppm (m, 5H, Ph); 13C NMR (CDCl3,
125 MHz): d=23.6, 26.6 (2q, Me), 37.3 (q, Ms), 57.7 (d, C-5), 58.4 (t,
NCH2), 68.2 (d, C-1), 68.8 (t, 8-CH2), 69.2 (t, C-4), 72.9 (d, C-8), 78.6 (s,
C-6), 127.9, 128.5, 129.1, 135.2 (3d, s, Ph), 207.5 ppm (s, CO); IR (KBr):
n˜ =3090–3030 (=C-H), 2980–2880 (C-H), 1730 (C=O), 1340 cmꢀ1 (SO2);
elemental analysis calcd (%) for C17H23NO6S (369.4): C 55.27, H 6.28, N
3.79; found C 54.90, H 6.01, N 3.43.
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CO2H); IR (film): n˜ =3490–3340 (O H, N H), 3090–3000 (=C-H), 2980–
ꢀ1
ꢀ
2930 (C H), 1740, 1730 cm (C=O); HRMS (EI, 80 eV): m/z: calcd for
(1R,5S,8R,9S)-8-Azidomethyl-2-benzyl-6,6-dimethyl-3,7-dioxa-2-aza-
ACHUTNGRENUbNG icycloHCATUNGTRENN[UGN 3.3.1]nonan-9-ol (32): Compound 31 (713 mg, 1.93 mmol) was dis-
C27H45NO7Si: 523.2965; found 523.2956 [M]+.
(1R,5S,8S,9S)-2-Benzyl-6,6-dimethyl-8-[(prop-2-ynyloxy)methyl]-3,7-di-
ACHTUNGTRENNUNGoxa-2-azabicycloACHTUNGTRENNUNG[3.3.1]nonan-9-ol (30): To a solution of NaOH (2.77 g,
solved in ethanol (20 mL). The solution was cooled to 08C and NaBH4
(130 mg, 3.44 mmol) was added. The resulting mixture was stirred for 3 h
at RT. Then, the solvent was removed in vacuo and the residue was dis-
solved in CH2Cl2 and H2O. The layers were separated and the aqueous
phase was extracted 2ꢄ with CH2Cl2. The combined organic layers were
dried with MgSO4, filtered and concentrated to dryness giving
(1R,5S,8S,9S)-methanesulfonic acid 2-benzyl-9-hydroxy-6,6-dimethyl-3,7-
70.0 mmol) in H2O (10 mL) was added CH2Cl2 (10 mL), compound 2
(415 mg, 1.40 mmol), TBAI (197 mg, 0.500 mmol) and propargyl bromide
(80% wt in toluene, 1.4 mL, 7.0 mmol). The mixture was stirred for 7 d
at RT. After extraction of the mixture 3ꢄ with CH2Cl2 the combined or-
ganic layers were dried (Na2SO4) and concentrated. Purification by
column chromatography (Al2O3, hexane/EtOAc 15:1) yielded (1S,5S,8S)-
2-benzyl-8-((prop-2-ynyloxy)methyl)-6,6-dimethyl-3,7-dioxa-2-azabicyclo-
dioxa-2-azabicycloACTHUNRGTNEUNG[3.3.1]non-8-ylmethyl ester (672 mg, 98%) as colorless
crystals. A solution of the obtained product (360 mg, 1.01 mmol) in DMF
(3 mL) was treated with NaN3 (196 mg, 3.03 mmol). The reaction mixture
was heated to 808C and stirred for 6 h at this temperature. Then EtOAc
(3 mL) was added and the mixture was washed with water, dried with
Na2SO4 and concentrated. Recrystallization (hexane/EtOAc 2:1) yielded
the pure product 32 (261 mg, 81%) as colorless crystals. M.p. 146–1498C;
[a]2D2 =+83.9 (c=0.25, CHCl3); 1H NMR (CDCl3, 500 MHz): d=1.32,
1.51 (2s, 3H each, Me), 1.58 (m, 1H, 5-H), 2.16 (brs, 1H, OH), 2.57 (t,
J=1.7 Hz, 1H, 1-H), 3.34 (dd, J=5.6, 12.2 Hz, 1H, 4-H), 3.72 (dd, J=
7.3, 12.2 Hz, 1H, 4-H), 4.05 (d, J=13.3 Hz, 1H, NCH2), 4.08 (dd, J=2.4,
12.3 Hz, 1H, 8-CH2), 4.16 (dd, J=1.9, 12.3 Hz, 1H, 8-CH2), 4.31 (d, J=
13.3 Hz, 1H, NCH2), 4.31 (m, 1H, 8-H), 4.68 (m, 1H, 9-H), 7.25–
7.34 ppm (m, 5H, Ph); 13C NMR (CDCl3, 125 MHz): d=26.4, 29.4 (2q,
Me), 42.6 (d, C-5), 52.6 (t, C-4), 57.8 (t, NCH2), 64.4 (d, C-1), 66.0 (d, C-
9), 67.5 (t, 8-CH2), 73.5 (d, C-8), 78.5 (s, C-6), 127.5, 128.4, 128.6,
137.4 ppm, (3d, s, Ph); IR (KBr): n˜ =3450 (O-H), 3090–3030 (=C-H),
2980–2850 (C-H), 2100 cmꢀ1 (N3); HRMS (EI, 80 eV, 1208C): m/z: calcd
for C16H22N4O3: 318.1692; found 318.1686 [M]+.
ACHTUNGTRENNUNG
[3.3.1]nonan-9-one (374 mg, 72%) as colorless oil. [a]2D2 =+77.0 (c=1.00,
CHCl3); 1H NMR (CDCl3, 500 MHz): d=1.21, 1.41 (2s, 3H each, Me),
ꢂ
2.33 (m, 1H, 5-H), 2.37 (t, J=2.3 Hz, 1H, C CH), 3.23 (m, 1H, 1-H),
3.78 (dd, J=5.6, 9.1 Hz, 1H, 4-H), 3.90 (dd, J=7.0, 9.1 Hz, 1H, 4-H),
3.97 (d, J=13.6 Hz, NCH2), 4.13 (m, 2H, NCH2, 8-H), 4.08 (d, J=
ꢂ
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15.8 Hz, 1H, CH2C CH), 4.09 (d, J=15.8 Hz, 1H, CH2C CH), 4.47 (dt,
J=5.5, 12.1 Hz, 1H, 8-CH2), 4.54 (dd, J=2.9, 12.1 Hz, 1H, 8-CH2), 7.25–
7.37 ppm (m, 5H, Ph); 13C NMR (CDCl3, 125 MHz): d=23.8, 26.7 (2 q,
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Me), 58.0 (t, NCH2), 58.6 (t, CH2C CH), 59.9 (d, C-5), 68.9 (d, C-1), 69.1
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(t, 8-CH2), 70.2 (t, C-4), 74.1 (d, C-8), 74.8 (s, C-6), 78.4 (s, C CH), 79.3
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(d, C CH), 127.6, 128.3, 128.8, 136.2 (3 d, s, Ph), 207.9 ppm (s, CO); IR
ꢀ1
ꢂ
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(film): n˜ =3280 ( C-H), 3090–2870 (=C-H, C-H), 2120 (C C), 1730 cm
(C=O); HRMS (EI, 80 eV): m/z: calcd for C19H23NO4: 329.1627; found
329.1620 [M]+.
NaBH4 (35 mg, 0.93 mmol) was added to a solution of the obtained prod-
uct (90 mg, 0.27 mmol) in EtOH (5 mL) at 08C. The reaction was stirred
for 1.5 h at that temperature. The solvent was removed in vacuo and
CH2Cl2 and H2O were added. The organic layer was separated and the
aqueous layer was extracted 2ꢄ with CH2Cl2. The combined organic
layers were dried with MgSO4 and concentrated in vacuo. Purification by
column chromatography yielded 30 (80 mg, 89%) as colorless crystals.
Compound 33: To a solution of alkyne 30 (30 mg, 0.09 mmol) and azide
32 (30 mg, 0.090 mmol) in MeCN (2.5 mL) were added solutions of NEt3
(1.9 mL, 0.02 mmol, 10 mm in MeCN), TBTA (1.9 mL, 0.02 mmol, 10 mm
in MeCN), and CuI (1.9 mL, 0.02 mmol, 10 mm in MeCN). Argon was
Chem. Eur. J. 2009, 15, 11632 – 11641
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11639