Synthesis of trans-6-Alkylpipecolic Acids
J . Org. Chem., Vol. 67, No. 8, 2002 2427
127.5, 72.7, 63.6, 60.9, 47.1, 35.3, 31.3, 20.8, 20.7, -2.3. Anal.
Calcd for C20H31NO2Si: C, 69.52; H, 9.04; N, 4.05. Found: C,
69.34; H, 8.92; N, 4.00.
4.06 (m, 0.65H), 3.02-2.90 (m, 0.65H), 2.87-2.65 (m, 1.35H),
0.08 (s, 9H). 13C NMR: 166.9 (maj), 165.9, 143.2, 142.6, 141.2,
138.8, 137.8, 137.4, 134.8, 134.4, 134.0, 133.7, 132.3, 129.4,
128.4, 71.8, 70.6, 69.9 (maj), 67.7 (maj), 63.5, 62.6 (maj), 60.4
[4(1S),5S]-4-(1-ter t-Bu tyl-4-tr im eth ylsila n ylbu t-3-en yl)-
5-p h en ylm or p h olin -2-on e (8c). Oil (Et2O/PE 10/90). Yield:
(maj), 58.0, 38.5, 36.1 (maj), -1.3. HRMS: calcd for C29H34
-
74%. [R]20D: -10 (c 0.6, CHCl3). H NMR: 7.28-7.15 (m, 5H),
NO2SSi (M + H+) m/z ) 488.2080, obsd m/z ) 488.2083.
1
6.00-5.87 (m, 1H), 5.71-5.64 (m, 1H), 4.23-4.02 (m, 3H), 3.82
(AB, J ) 17.5 Hz, 1H), 3.69 (AB, J ) 17.5 Hz, 1H), 2.41-2.23
(m, 3H), 0.68 (s, 9H), 0,03 (s, 9H). 13C NMR: 170.7, 146.7,
138.3, 132.6, 129.0, 128.5, 71.7, 67.2, 62.8, 48.9, 36.0, 34.0, 28.8,
-1.3. Anal. Calcd for C21H33NO2Si: C, 70.14; H, 9.25; N, 3.90.
Found: C, 70.14; H, 9.44; N, 3.73.
Gen er a l P r oced u r e for t h e Cycliza t ion of La ct on es
(10). A solution of aminothioether (0.44 mmol) and zinc
chloride (0.2 g, 0.88 mmol) in CH2Cl2 (9 mL) was stirred for 1
h 30 at room temperature. The mixture was then poured into
water (20 mL) and extracted with CH2Cl2. The organic layers
were dried on MgSO4, evaporated, and chromatographed to
give the corresponding bicyclic compounds.
(4S,6R,9a S)-4-P h en yl-6-p r op yl-3,4,7,9a -tetr a h yd r o-6H-
p yr id o[2,1-c][1,4]oxa zin -1-on e (10a ). Oil (Et2O/PE 10/90).
Yield: 79%. [R]20D: -93 (c 0.6, CHCl3). 1H NMR: 7.34-7.27
(m, 5H), 5.92-5.84 (m, 1H), 5.70-5.64 (m, 1H), 4.47-4.42 (m,
1H), 4.23 (t, J ) 10.7 Hz, 1H), 4.10 (dd, J ) 10.7, 3.2 Hz, 1H),
4.02 (dd, J ) 10.7, 3.2 Hz, 1H), 2.70-2.62 (m, 1H), 2.14-2.02
(m, 1H), 1.57-1.48 (m, 1H), 1.44-1.06 (m, 4H), 0.77 (t, J )
7.2 Hz, 3H). 13C NMR: 170.2, 136.5, 128.9, 128.7, 128.6, 127.1,
123.6, 74.0, 57.4, 55.6, 50.5, 34.1, 22.9, 19.3, 14.2. Anal. Calcd
for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.37;
H, 7.96; N, 4.98.
(4S,6S,9a S)-4-P h en yl-6-isop r op yl-3,4,7,9a -tetr a h yd r o-
6H-p yr id o[2,1-c][1,4]oxa zin -1-on e (10b). Solid (Et2O/PE
8/92). Yield: 78%. Mp: 75 °C. [R]20D: -69 (c 1.2, CHCl3). 1H
NMR: 7.39-7.32 (m, 5H), 5.94-5.90 (m, 1H), 5.74-5.68 (m,
1H), 4.45-4.40 (m, 1H), 4.24 (t, J ) 10.5 Hz, 1H), 4.08 (dd, J
) 10.7, 3.2 Hz, 1H), 4.04 (dd, J ) 10.5, 3.2 Hz, 1H), 2.17 (dd,
J ) 10.5, 6.0 Hz, 1H), 2.11-1.92 (m, 1H), 1.80-1.67 (m, 2H),
0.96 (d, J ) 6.5 Hz, 3H), 0.66 (d, J ) 6.5 Hz, 3H). 13C NMR:
170.1, 136.5, 128.9, 128.7, 127.0, 124.1, 74.0, 57.5, 57.4, 55.8,
27.2, 20.6, 20.2, 19.3. Anal. Calcd for C17H21NO2: C, 75.25; H,
7.80; N, 5.16. Found: C, 75.12; H, 7.80; N, 5.09.
(4S,6S,9a S)-6-ter t-Bu tyl-4-p h en yl-3,4,7,9a -tetr a h yd r o-
6H-pyr ido[2,1-c][1,4]oxazin -1-on e (10c) an d (4S,6S,8R,9R,-
9a S)-6-ter t-Bu t yl-4-p h en yl-8-p h en ylsu lfa n yl-9-t r im et h -
ylsila n ylh exa h yd r op yr id o[2,1-c][1,4]oxa zin -1-on e (12).
Com p ou n d 10c. Oil (Et2O/PE 10/90). Yield: 62%. [R]20D: -110
(c 0.5, CHCl3). 1H NMR: 7.29-7.22 (m, 5H), 5.98-5.91 (m,
1H), 5.68-5.62 (m, 1H), 4.57-4.52 (m, 1H), 4.27 (t, J ) 10.7
Hz, 1H), 4.06 (dd, J ) 10.7, 3.2 Hz, 1H), 3.94 (dd, J ) 10.7,
3.2 Hz, 1H), 2.27 (d, J ) 7.7 Hz, 1H), 2.02-1.89 (m, 1H), 1.75-
1.63 (m, 1H), 0.78 (s, 9H). 13C NMR: 170.5, 137.0, 129.0, 128.8,
128.7, 123.8, 73.9, 58.6, 58.3, 57.5, 34.9, 28.5, 18.6. HRMS:
calcd for C18H24NO2 (M + H+) m/z ) 286.1807, obsd m/z )
286.1805.
[4(1S),5S]-5-P h en yl-4-(1-p h en yl-4-tr im eth ylsila n ylbu t-
3-en yl)m or p h olin -2-on e (8d ). Oil (Et2O/PE 10/90). Yield:
1
66%. [R]20D: +9 (c 1.8, CHCl3). H NMR: 7.53-7.44 (m, 5H),
7.39-7.33 (m, 5H), 5.80 (dt, J ) 18.5, 5.5 Hz, 1H), 5.68 (d, J
) 18.5 Hz, 1H), 4.44-4.38 (m, 2H), 4.30 (m, 1H), 3.93 (dd, J
) 6.5, 7.5 Hz, 1H), 3.62 (s, 2H), 2.78-2.72 (m, 2H), 0.00 (s,
9H). 13C NMR: 169.5, 142.8, 139.6, 137.3, 133.6, 129.1, 128.7,
128.5, 128.4, 127.5, 72.5, 62.1, 59.9, 47.7, 33.7, -1.3. Anal.
Calcd for C23H29NO2Si: C, 72.78; H, 7.70; N, 3.69. Found: C,
72.50; H, 8.05; N, 3.38.
Gen er a l P r oced u r e for Th iop h en yla tion of La cton es
9. Lithium bis(trimethylsilyl)amide (2.66 mL, 2.66 mmol, 1 M
in THF) was added at -45 °C to a solution of lactone (1.33
mmol) in THF (11 mL). After the solution was stirred at this
temperature for 15 min, a solution of diphenyl disulfide (0.511
g, 2.34 mmol) in THF (4 mL) was added dropwise, and the
mixture was allowed to reach slowly 0 °C and hydrolyzed with
NH4Cl (15 mL). The aqueous layer was extracted twice with
Et2O, and the organic layers were dried over MgSO4 and
evaporated. The residue was chromatographed to afford cor-
responding lactones as a various mixture of diastereoisomers
at C-3.
[4(1R),5S]-5-P h en yl-3-p h en ylsu lfa n yl-4-(1-p r op yl-4-tr i-
m eth ylsilan ylbu t-3-en yl)m or ph olin -2-on e (9a). Solid (Et2O/
PE 3/97). Yield: 66%. 1H NMR: 7.59-7.56 (m, 2H), 7.47-7.35
(m, 8H), 5.89 (dt, J ) 6.5, 18.5 Hz, 1H), 5.67 (d, J ) 18.5 Hz,
1H), 5.06 (s, 1H), 4.80 (t, J ) 11.5 Hz, 1H), 4.30 (dd, J ) 4.2,
11.5 Hz, 1H), 4.20 (dd, J ) 4.2, 11.5 Hz, 1H), 2.73-2.62 (m,
1H), 2.39-2.28 (m, 1H), 2.18-2.07 (m, 1H), 1.66-1.44 (m, 2H),
1.38-1.26 (m, 1H), 1.20-1.08 (m, 1H), 0.72 (t, J ) 7.0 Hz, 3H),
0.03 (s, 9H). 13C NMR: 166.0, 143.1, 137.6, 134.5, 134.3, 132.7,
129.3, 129.0, 128.7, 128.9, 128.4, 69.9, 66.9, 60.8, 59.2, 39.2,
35.4, 20.1, 13.9, -1.3. Anal. Calcd for C26H35NO2SSi: C, 68.83;
H, 7.78; N, 3.09. Found: C, 68.81; H, 7.94; N, 2.93.
[4(1S),5S]-4-(1-Isop r op yl-4-tr im eth ylsila n ylbu t-3-en yl)-
5-p h en yl-3-p h en ylsu lfa n ylm or p h olin -2-on e (9b ). Solid
(Et2O/PE 3/97). Yield: 73%. 1H NMR: 7.55-7.45 (m, 2H),
7.35-7.28 (m, 8H), 6.01 (ddd, J ) 18.5, 7.4, 5.5 Hz, 1H), 5.76-
5.68 (m, 1H), 5.08 (s, 1H), 4.91 (t, J ) 11.7 Hz, 1H), 4.32 (dd,
J ) 11.7, 4.0 Hz, 1H), 4.18 (dd, J ) 11.7, 4.3 Hz, 1H), 2.62-
2.42 (m, 3H), 1.83-1.67 (m, 1H), 0.99 (d, J ) 6.5 Hz, 3H), 0.82
(d, J ) 6.5 Hz, 3H), 0.07 (s, 9H). 13C NMR: 165.9, 144.0, 137.5,
134.5, 134.1, 132.6, 129.4, 129.0, 128.9, 128.8, 69.7, 67.9, 66.2,
62.0, 37.8, 32.0, 21.5, 20.5, -1.3. HRMS: calcd for C26H36NO2-
SSi (M + H+) m/z ) 454.2236, obsd m/z ) 454.2239.
[4(1S),5S]-4-(1-ter t-Bu tyl-4-tr im eth ylsila n ylbu t-3-en yl)-
5-p h en yl-3-p h en ylsu lfa n ylm or p h olin -2-on e (9c). Solid
(Et2O/PE: 3/97). Yield: 55%. 1H NMR: 7.48-7.44 (m, 2H),
7.31-7.24 (m, 8H), 6.00 (ddd, J ) 18.5, 7.8, 5.2 Hz, 1H), 5.68
(d, J ) 18.5 Hz, 1H), 5.01 (s, 1H), 5.01 (t, J ) 12.0 Hz, 1H),
4.22 (dd, J ) 12.0, 4.5 Hz, 1H), 4.04 (dd, J ) 12.0, 4.5 Hz,
1H), 2.45 (dd, J ) 9.5, 3.5 Hz, 1H), 2.40-2.25 (m, 2H), 0.76 (s,
9H), 0.01 (s, 9H). 13C NMR: 165.9, 144.9, 137.6, 134.6, 134.2,
132.0, 129.4, 129.3, 129.1, 128.9, 128.7, 69.8, 69.2, 68.2, 63.4,
35.9, 28.4, -1.3. HRMS: calcd for C27H38NO2SSi (M + H+) m/z
) 468.2393, obsd m/z ) 468.2390.
Com p ou n d 12. Oil (Et2O/PE 10/90). Yield: 18%. [R]20D: -23
(c 0.8, CHCl3). 1H NMR: 7.47-7.43 (m, 2H), 7.31-7.11 (m,
8H), 5.16 (dd, J ) 4.2, 11.2 Hz, 1H), 4.38 (dd, J ) 2.2, 4.0 Hz,
1H), 4.28 (dd, J ) 2.2, 11.5 Hz, 1H), 4.04 (d, J ) 11.7 Hz, 1H),
3.77-3.74 (m, 1H), 2.86 (dd, J ) 6.5, 11.5 Hz, 1H), 1.80 (ddd,
J ) 4.0, 6.0, 14.5 Hz, 1H), 1.56 (ddd, J ) 3.5, 11.5, 15.0 Hz,
1H), 1.41 (d, J ) 11.0 Hz, 1H), 0.45 (s, 9H), 0.00 (s, 9H). 13C
NMR: 171.4, 144.1, 134.6, 133.6, 129.2, 129.0, 128.3, 128.1,
127.7, 127.3, 72.3, 66.2, 64.0, 56.5, 44.7, 36.1, 29.9, 26.8, 25.8,
-2.2. Anal. Calcd for C27H37NO2SSi: C, 69.33; H, 7.97; N, 2.99.
Found: C, 69.38; H, 8.07; N, 3.01.
(4S,6S,9aS)-4,6-Diph en yl-3,4,7,9a-tetr ah ydr o-6H-pyr ido-
[2,1-c][1,4]oxa zin -1-on e (10d ). Oil (Et2O/PE 20/80). Yield:
83%. [R]20D: -70 (c 2.4, CHCl3). 1H NMR: 7.35-7.15 (m, 10H),
6.06 (ddd, J ) 3.7, 6.7, 10.2 Hz, 1H), 5.77 (ddd, J ) 2.2, 5.0,
10.2 Hz, 1H), 4.35 (dd, J ) 9.0, 11.0 Hz, 1H), 4.27 (dd, J )
4.0, 11.0 Hz, 1H), 4.12-4.04 (m, 2H), 3.84 (t, J ) 4.7 Hz, 1H),
2.28-2.19 (m, 2H). 13C NMR: 170.3, 140.5, 137.4, 129.0, 128.5,
128.4, 128.1, 128.0, 127.6, 127.2, 124.4, 71.8, 57.8, 56.6, 55.9,
25.6. HRMS: calcd for C20H20NO2 (M + H+) m/z ) 306.1494,
obsd m/z ) 306.1492.
[4(1S),5S]-5-P h en yl-3-p h en ylsu lfa n yl-4-(1-p h en yl-4-tr i-
m eth ylsila n ylbu t-3-en yl)m or p h olin -2-on e (9d ). Oil (Et2O/
PE 3/97). Yield: 38% (mixture of two inseparable diastereoi-
somers at the C-3 center in a 65/35 ratio). 1H NMR: 7.62-
7.18 (m, 15 H), 6.00-5.71 (m, 2H), 5.18 (s, 0.35H), 5.13 (dd, J
) 4.7, 12.2 Hz, 0.35H), 5.01 (s, 0.65H), 4.82 (t, J ) 11.7 Hz,
0.65H), 4.52 (dd, J ) 4.2, 5.7 Hz, 0.65H), 4.33-4.22 (m, 1.70H),
Gen er a l P r oced u r e for th e Hyd r ogen olysis of Bicyclic
La cton es. A solution of lactone (0.15 mmol) in absolute
ethanol (1.5 mL) was injected into a hydrogenation flask
containing a prehydrogenated suspension of 20% Pd(OH)2/C
(Pearlman catalyst) (0.04 g) in absolute ethanol (1.5 mL). The
hydrogenation was complete in 4-6 h. The mixture was