598 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Thai et al.
2H), 1.44 (br s, 11H); 13C NMR (CDCl3) δ 199.2, 163.3, 155.8,
130.6, 128.5, 113.7, 79.91, 56.67, 55.45, 42.58, 28.36, 26.50,
25.11, 19.96. Anal. (C18H25NO4) H, N; C: calcd, 67.69; found,
67.10.
× 10 mL). The combined EtOAc layers were dried, filtered,
and evaporated to an oil which was purified by silica gel
chomatography eluting with 16-20% EtOAc in hexanes. The
less polar (1R,2R)-9 was obtained as a white solid (78 mg, 64%
1
yield): mp 80-81 °C; [R]20 +12.4° (c 2.20, CH2Cl2); H NMR
1-[(2R)-N-(ter t-Bu tyloxycar bon yl)piper idin -2-yl]-1-ph e-
n yleth en e (8). To a suspension of methyltriphenylphospho-
nium bromide (230 mg, 0.644 mmol) in THF (1.0 mL) was
added solid potassium tert-butoxide (72.2 mg, 0.644 mmol), and
the resulting yellow suspension was allowed to stir for 10 min.
A solution of (R)-7 (124 mg, 0.429 mmol) in THF (2.0 mL) was
then added dropwise via syringe and the reaction allowed to
proceed for 5 min. The reaction was quenched with H2O (1.0
mL) and suspended between EtOAc (15 mL) and H2O (15 mL).
The aqueous layer was extracted with EtOAc (2 × 15 mL).
The combined EtOAc layers were dried, filtered, and evapo-
rated to an oil which was then filtered though a plug of silica
gel eluting with 9% EtOAc in hexanes to give 115 mg (93%) of
(R)-8 as a colorless oil: [R]20D -28.3° (c 1.16, CH2Cl2); 1H NMR
(CDCl3) δ 7.30 (m, 3H), 7.27 (m, 2H), 5.26 (br s, 2H), 5.04 (s,-
1H), 3.95 (m, 1H), 2.89 (t, J ) 10, 1H), 1.78 (d, J ) 2.9, 1H),
1.62 (m, 2H), 1.45 (s, 9H), 1.26 (br s, 3H); 13C NMR (CDCl3) δ
155.4, 148.2, 141.4, 128.2, 127.3, 127.0, 124.4, 114.1, 79.42,
40.27, 28.44, 26.81, 25.46, 19.18. Anal. (C18H25NO2) C, H, N.
1-(2S)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-1-p h e-
D
(CDCl3) δ 7.29 (m, 5H), 4.60 (d, J ) 12, 1H), 4.00 (d, J ) 13,
1H), 3.70 (m, 2H), 3.52 (m, 2H), 3.03 (d, J ) 12, 2H), 2.81 (t,
J ) 11, 1H), 1.60 (m, 2H), 1.46 (s, 9H), 1.39 (br s, 2H); 13C
NMR (CDCl3) δ 156.5, 141.3, 128.9, 128.6, 126.8, 80.39, 63.54,
50.33, 45.88, 39.92, 28.49, 26.09, 25.43, 18.88. The more polar
(1S,2R)-9 (30 mg, 25% yield) was obtained as a colorless oil:
[R]20D +52.3° (c 1.06, CH2Cl2); 1H NMR (CDCl3) δ 7.32 (m, 5H),
4.57 (m, 1H), 3.87 (m, 3H), 3.27 (m, 1H), 2.61 (m, 1H), 1.83
(m, 1H), 1.70 (m, 3H), 1.36 (s, 9H), 1.34 (br s, 2H).
(1S)-1-[(2S)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-
1-p h en yl-2-h yd r oxyeth a n e a n d (1R)-1-[(2S)-N-(ter t-Bu -
t yloxyc a r b on yl)p ip e r id in -2-yl]-1-p h e n yl-2-h yd r oxy-
eth a n e (9): 61% yield of (1S,2S)-9 as a white solid, mp 78-
1
80 °C; [R]20 -11.1° (c 1.32, CH2Cl2); H NMR (CDCl3) δ 7.27
D
(m, 5H), 4.61 (d, J ) 11, 1H), 4.01 (d, J ) 12, 1H), 3.71 (m,
2H), 3.54 (m, 2H), 3.04 (d, J ) 11, 2H), 2.82 (t, J ) 12, 1H),
1.61 (m, 2H), 1.48 (s, 9H), 1.28 (br s, 2H); 13C NMR (CDCl3) δ
156.2, 141.2, 128.6, 128.3, 126.5, 80.10, 50.17, 45.67, 39.70,
28.28, 25.88, 25.23, 18.67. Anal. (C18H27NO3) C, H, N.
n yleth en e (8): 90% yield as a colorless oil; [R]20 +26.6° (c
(1S,2R)-9 was obtained as an oil in 21% yield: [R]20D -52.7°
(c 1.09, CH2Cl2); 1H NMR (CDCl3) δ 7.37 (m, 5H), 4.58 (m, 1H),
3.88 (m, 3H), 3.31 (m, 1H), 2.67 (m, 1H), 1.85 (m, 1H), 1.73
(m, 3H), 1.35 (s, 9H), 1.32 (br s, 2H). Anal. (C18H27NO3) C,
H, N.
D
1
1.59, CH2Cl2); H NMR (CDCl3) δ 7.30 (m, 3H), 7.27 (m, 2H),
5.26 (br s, 2H), 5.03 (s, 1H), 3.96 (m, 1H), 2.89 (t, J ) 8.9, 1H),
1.78 (d, J ) 3.2), 1H), 1.63 (m, 2H), 1.45 (s, 9H), 1.39 (br s,
3H); 13C NMR (CDCl3) δ 155.3, 148.1, 141.3, 128.1, 127.2,
126.9, 124.2, 114.0, 79.32, 40.17, 28.33, 26.69, 25.33, 19.05.
Anal. (C18H25NO2) C, H, N.
1-[(2R)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-1-(4-
br om op h en yl)eth en e (11): 95% yield as a colorless oil:
[R]20D -9.21° (c 3.28, CH2Cl2); 1H NMR (CDCl3) δ 7.43 (m, 2H),
7.20 (m, 2H), 5.27 (br s, 2H), 5.07 (s, 1H), 3.86 (d, J ) 3.0,
1H), 2.82 (m, 1H), 1.83 (m, 1H), 1.63 (m, 2H), 1.45 (s, 9H),
1.41 (br s, 3H); 13C NMR (CDCl3) δ 155.3, 147.3, 140.2, 132.0,
131.3, 128.7, 121.3, 114.8, 79.61, 40.34, 28.46, 26.72, 25.40,
19.15. Anal. (C18H24NO2Br) C, H, N.
(1R)-1-[(2R)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-
1-(4-br om op h en yl)-2-h yd r oxyeth a n e (12): 58% yield as a
white solid; mp 117-118 °C; [R]20 +7.28° (c 3.09, CH2Cl2);
D
1H NMR (CDCl3) δ 7.43 (m, 2H), 7.27 (m, 2H), 4.59 (d, J ) 12,
1H), 4.04 (d, J ) 13, 1H), 3.73 (m, 2H), 3.51 (t, J ) 12, 1H),
3.09 (d, J ) 12, 1H), 2.85 (t, J ) 13, 1H), 1.64 (br s, 1H), 1.50
(s, 9H), 1.47 (br s, 2H), 1.28 (m, 2H); 13C NMR (CDCl3) δ 156.6,
140.5, 131.6, 130.6, 120.6, 80.66, 63.18, 50.10, 45.25, 39.98,
28.51, 26.08, 25.38, 18.87. Anal. (C18H26NO3Br) C, H, N.
(1S)-1-[(2S)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-
1-(4-br om op h en yl)-2-h yd r oxyeth a n e (12): 56% yield as a
1-[(2S)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-1-(4-
br om op h en yl)eth en e (11): 93% yield as a colorless oil; [R]20
D
white solid; mp 114-117 °C; [R]20 -7.18° (c 3.51, CH2Cl2);
D
+7.55° (c 2.86, CH2Cl2); 1H NMR (CDCl3) δ 7.43 (m, 2H), 7.20
(m, 2H), 5.27 (br s, 2H), 5.07 (s, 1H), 3.86 (d, J ) 3.0, 1H),
2.82 (m, 1H), 1.84 (m, 1H), 1.63 (m, 2H), 1.46 (s, 9H), 1.36 (br
s, 3H); 13C NMR (CDCl3) δ 155.3, 147.2, 140.2, 132.0, 131.3,
128.7, 121.3, 114.8, 79.61, 40.34, 28.47, 26.69, 25.43, 19.15.
Anal. (C18H24NO2Br) H, N; C: calcd, 59.02; found, 59.54.
1-[(2R)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-1-(4-
m eth oxyp h en yl)eth en e (14): 98% yield as a colorless oil;
[R]20D -22.7° (c 2.87, CH2Cl2); 1H NMR (CDCl3) δ 7.28 (m, 2H),
6.87 (m, 2H), 5.25 (br s, 2H), 5.01 (s, 1H), 3.94 (m, 1H), 3.82
(s, 3H), 2.90 (m, 1H), 1.83 (m, 1H), 1.63 (m, 2H), 1.49 (br s,
12H); 13C NMR (CDCl3) δ 158.9, 155.4, 147.5, 133.7, 128.0,
113.5, 113.1, 79.32, 55.19, 53.51, 40.24, 28.40, 26.75, 25.43,
19.12. Anal. (C19H27NO3) C, H, N.
1H NMR (CDCl3) δ 7.44 (m, 2H), 7.27 (m, 2H), 4.59 (d, J ) 12,
1H), 4.04 (d, J ) 13, 1H), 3.71 (m, 2H), 3.51 (t, J ) 12, 1H),
3.02 (d, J ) 12, 1H), 2.82 (t, J ) 13, 1H), 1.59 (br s, 1H), 1.50
(s, 9H), 1.47 (br s, 2H), 1.26 (m, 2H); 13C NMR (CDCl3) δ 156.6,
140.5, 131.6, 130.6, 120.6, 80.66, 63.17, 50.08, 45.23, 39.99,
28.50, 26.11, 25.40, 18.85. Anal. (C18H26NO3Br) C, H, N.
(1R)-1-[(2R)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-
1-(4-m eth oxyp h en yl)-2-h yd r oxyeth a n e (15): 62% yield as
a white solid; mp 115-117 °C; [R]20 +4.12° (c 1.31, CH2Cl2);
D
1H NMR (CDCl3) δ 7.37 (m, 2H), 6.94 (m, 2H), 4.67 (d, J ) 11,
1H), 4.12 (d, J ) 13, 1H), 3.87 (s, 3H), 3.80 (m, 2H), 3.60 (br
s, 2H), 3.12 (d, J ) 10, 1H), 2.93 (t, J ) 11, 1H), 1.71 (m, 1H),
1.58 (s, 9H), 1.49 (m, 3H); 13C NMR (CDCl3) δ 158.3, 156.3,
133.3, 129.6, 113.9, 80.23, 63.57, 55.12, 50.41, 44.86, 39.82,
28.40, 25.95, 25.36, 18.79. Anal. (C19H29NO4) C, H, N.
1-(2S)-N-(ter t-Bu t yloxyca r b on yl)p ip er id in -2-yl]-1-(4-
m eth oxyp h en yl)eth en e (14): 96% yield as a colorless oil;
[R]20D +25.6° (c 1.07, CH2Cl2); 1H NMR (CDCl3) δ 7.28 (m, 2H),
6.87 (m, 2H), 5.24 (br s, 2H), 5.05 (s, 1H), 3.95 (m, 1H), 3.81
(s, 3H), 2.92 (m, 1H), 1.83 (m, 1H), 1.60 (m, 2H), 1.48 (br s,
12H); 13C NMR (CDCl3) δ 158.9, 155.4, 147.5, 133.7, 128.0,
113.5, 113.0, 79.32, 55.19, 53.60, 40.27, 28.40, 26.75, 25.43,
19.12. Anal. (C19H27NO3) C, H, N.
(1R)-1-[(2R)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-
1-p h en yl-2-h yd r oxyeth a n e a n d (1S)-1-[(2R)-N-(ter t-Bu -
t yloxyc a r b on yl)p ip e r id in -2-yl]-1-p h e n yl-2-h yd r oxy-
eth a n e (9). To a solution of (R)-8 (115 mg, 0.401 mmol) in
THF (2.0 mL) was added 1.0 M BH3‚THF (802 µL, 0.802 mmol)
dropwise at room temperature via syringe over ∼5 min. The
reaction mixture was then stirred for 4 h after which H2O (1.0
mL), 3 N NaOH (1.0 mL), and 30% H2O2 (2.0 mL) were added
consecutively. Stirring was continued overnight. The result-
ing mixture was suspended between EtOAc (20 mL) and H2O
(15 mL), and the aqueous layer was extracted with EtOAc (3
(1S)-1-[(2S)-N-(ter t-Bu tyloxyca r bon yl)p ip er id in -2-yl]-
1-(4-m eth oxyp h en yl)-2-h yd r oxyeth a n e (15): 64% yield as
a white solid; mp 116-117 °C: [R]20 -4.18° (c 1.22, CH2Cl2);
D
1H NMR (CDCl3) δ 7.37 (m, 2H), 6.94 (m, 2H), 4.66 (d, J ) 10,
1H), 4.11 (d, J ) 12, 1H), 3.86 (s, 3H), 3.80 (m, 2H), 3.60 (br
s, 2H), 3.12 (d, J ) 11, 1H), 2.92 (t, J ) 11, 1H), 1.70 (m, 1H),
1.58 (s, 9H), 1.44 (m, 3H); 13C NMR (CDCl3) δ 158.3, 156.3,
133.3, 129.6, 113.9, 80.23, 63.57, 55.13, 50.42, 44.86, 39.82,
28.41, 25.95, 25.37, 18.79. Anal. (C19H29NO4) C, H, N.
(2R,2′R)-Meth ylp h en id a te Hyd r och lor id e (1). (1R,2R)-
Alcohol 9 (228 mg, 0.748 mmol) was dissolved in DMF (3.0
mL), and PDC (984 mg, 2.62) was added. After 17 h of stirring,
the reaction was quenched with H2O (40 mL) and the resulting
mixture extracted with Et2O (6 × 20 mL). Combined Et2O
layers were then extracted with 0.5 N NaOH (4 × 30 mL) and
the alkaline solution brought to pH ) 2.0 with 3 N HCl. A
white precipitate formed and was extracted into EtOAc (4 ×