Total Synthesis of (-)-Indolizidine 195B
(55:35:10 hexanes/ethyl acetate/iso-propanol) afforded 16 (0.150
g, 70%) as a white solid: mp ) 118-121 °C; 1H NMR (300 MHz,
CDCl3) δ 7.35-7.24 (m, 5H), 5.83 (ddd, J ) 17.1, 10.5, 5.7 Hz,
1H), 5.33 (apparent dt, J ) 17.6, 1.3 Hz, 1H), 5.14 (apparent dt, J
) 10.5, 1.3 Hz, 1H), 4.34 (m, 1H), 3.82 (ABq, J ) 12.7 Hz, ∆V )
20.6 Hz, 2H), 3.58 (m, 2H), 3.03 (br s, 3H), 2.62 (dt, J ) 7.9, 3.9
Hz, 1H), 1.73-1.44 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 139.4,
137.9, 128.5, 128.3, 127.2, 116.2, 71.7, 62.7, 61.1, 51.3, 29.9, 26.9;
IR (neat) (br) 3304, 2937, 1641 cm-1; MS (DCI/NH3) m/z 236
(MH+, 100), 218 (10), 178 (17); HRMS calcd for C14H22NO2
(MH+) 236.1650, found 236.1642; [R]25D ) + 5.3 (c 0.898, CH2-
Cl2).
Et3N) afforded 20 (15.2 mg, 47%) as a clear oil: 1H NMR (300
MHz, CDCl3) δ 7.41-7.19 (m, 5H), 5.74 (m, 1H), 5.63 (dm, J )
10.1 Hz, 1H), 3.87 (ABq, J ) 14.0 Hz, ∆V ) 30.0 Hz, 2H), 3.71-
3.50 (m, 4H), 2.39 (br m, 2H), 1.70-1.56 (m, 4H), 1.29 (m, 3H),
1.69-0.99 (m, 39H); 13C NMR (75 MHz, CDCl3) δ 173.6, 140.2,
130.9, 128.6, 128.1, 126.7, 122.7, 63.6, 56.8. 56.3, 54.3, 29.7, 29.6,
28.0, 18.0, 17.8, 12.0; IR (neat) 2943, 2808, 1717, 1654, 1260 cm-1
;
MS (FAB/DCM/NBA) m/z 588 (MH+, 54), 548 (33), 547 (52),
433 (32), 387 (37), 386 (100), 154 (84), 137 (41), 136 (45); HRMS
calcd for C34H62NO3Si2 (MH+) 588.4268, found 588.4294; [R]23
) +18.8 (c 0.52, CH2Cl2).
D
(2R,6S)-1-Benzyl-2-methyl-6-[(3-triisopropylsilyloxy)propyl]-
1,2,3,6-tetrahydropyridine (21). Methylsulfonyl chloride (0.0206
mL, 0.266 mmol) was added dropwise to a stirred 0 °C solution of
9 (74.0 mg, 0.177 mmol) and triethylamine (0.0543 mL, 0.390
mmol) in ether (2 mL). The reaction mixture was allowed to warm
to rt, stirred for 2 h, then filtered through Celite. The residue was
washed with dry ether, then the combined organic layers were
cooled to 0 °C and LiAlH4 (70.7 mg, 1.77 mmol) was added. The
suspension was allowed to warm to rt and stirred for 1 h. The
reaction mixture was cooled to 0 °C, then H2O (0.071 mL), 15%
NaOH (0.071 mL), and H2O (0.21 mL) were added sequentially
and the resulting suspension was stirred at rt for 1 h. Filtration
through Celite followed by concentration afforded crude product
(63.7 mg) as light yellow oil. Flash chromatography (9:1 hexanes/
ethyl acetate, 2% triethylamine) afforded methyl piperidine 21 (54.2
mg, 76%) as clear oil: 1H NMR (300 MHz, CDCl3) δ 7.39 (d, J
) 7.2 Hz, 2H), 7.28 (t, J ) 7.2 Hz, 2H), 7.19 (t, J ) 7.2 Hz, 1H),
5.75 (m, 1H), 5.62 (dm, J ) 10.2 Hz, 1H), 3.78 (ABq, J ) 15.6
Hz, ∆V ) 23.1 Hz, 2H), 3.59 (m, 2H), 3.12 (br m, 1H), 2.88 (m,
1H), 2.09 (br dm, J ) 15.9 Hz, 1H), 1.90 (br dm, J ) 15.6 Hz,
1H), 1.66-1.47 (m, 4H), 1.09-1.00 (m, 24H); 13C NMR (75 MHz,
CDCl3) δ 142.0, 129.6, 128.0, 126.2, 124.0, 63.5, 60.3, 56.0, 52.9,
32.1, 30.7, 29.3, 21.5, 18.0, 12.0; IR (CH2Cl2) 2989, 2942, 2865,
1280 cm-1; MS (DCI/NH3) m/z 402 (MH+, 100), 186 (7); HRMS
(2S,6S)-N-Phenylmethyl-6-[[(2-triisopropylsilyl)oxy]carbonyl]-
2-[[(3-triisopropylsilyl)oxy]propyl]-1-2,5,6-tetrahydropyridine
(17). Triisopropylsilyltriflate (0.56 mL, 1.14 mmol) was added to
a stirring solution of morpholinone 10 (0.273 mg, 0.993 mmol)
and triethylamine (0.692 mL, 4.96 mmol) in benzene (10 mL) at
rt. The resulting suspension was stirred for 6 h at rt then
concentrated to approximately 2 mL. Filtration (silica gel, 9:1
hexanes/ethyl acetate/2% triethylamine) afforded crude pipecolic
ester 17 (0.562 mg, 96%) as a pale yellow oil that was used in the
next step without further purification. Flash chromatography (9:1
hexanes/ethyl acetate) of a similar sample afforded an analytical
sample of 17 as a colorless oil: 1H (300 MHz, CDCl3) δ 7.40 (d,
J ) 6.6 Hz, 2H), 7.25 (m, 3H), 5.77 (m, 1H), 5.65 (dm, J ) 10.1
Hz, 1H), 3.97 (ABq, J ) 14.5 Hz, ∆V ) 25.0 Hz, 2H), 3.54 (m,
3H), 3.20 (br m, 1H), 2.45 (dm, J ) 16.7 Hz, 1H), 2.29 (dm, J )
15.8 Hz, 1H) 1.71-1.44 (m, 4H), 1.30 (m, 3H), 1.09-1.03 (m,
39H); 13C (75 MHz, CDCl3) δ 174.3, 138.9, 129.7, 129.0 128.1,
126.9, 122.7, 63.5, 59.7, 57.8, 57.1, 29.2, 29.0, 27.4, 18.0, 17.9,
12.0; IR (CH2Cl2) 3074, 3039, 2946, 1707 cm-1; MS (FAB+, ether,
NBA, PEG) m/z 588 (MH+, 59), 587 (15), 586 (30), 386 (100),
372 (36), 370 (13), 170 (28); HRMS calcd for C34H62NO3Si2 (MH+)
588.4268, found 588.4237; [R]23 ) -1.1 (c 0.73, CH2Cl2).
D
(5S,6R)-4-Benzyl-5-[(3-hydroxy)propyl]-6-vinylmorpholin-2-
one (18). A solution of phenyl bromoacetate (60.0 mg, 0.279 mmol)
in CH3CN (1 mL) was added dropwise to a stirred 0 °C solution
of amino alcohol 16 (54.7 mg, 0.232 mmol), CH3CN (3 mL), and
N,N-diisopropylethylamine (0.121 mL, 0.698 mmol). The resulting
solution was warmed to rt then stirred for 5 days. The solution
was concentrated to dryness, ethyl acetate (10 mL) was added, and
the mixture was stirred for 1 h at rt. Filtration followed by
concentration afforded crude product (140.8 mg) as yellow oil. Flash
chromatography (1:1 hexanes/ethyl acetate, 2% triethylamine)
afforded lactone 18 (20.3 mg, 32%) as clear oil: 1H NMR (300
MHz, CDCl3) δ 7.36-7.28 (m, 5H), 5.85 (ddd, J ) 16.7, 10.5, 5.7
Hz, 1H), 5.43 (apparent dt, J ) 17.6, 1.3 Hz, 1H), 5.32 (apparent
dt, J ) 10.5, 1.3 Hz, 1H), 5.16 (ddt, J ) 5.7, 3.1, 1.3 Hz, 1H),
3.79 (ABq, J ) 13.2 Hz, ∆V ) 35.6 Hz, 2H), 3.62 (dt, J ) 3.1, 2.6
Hz, 2H), 3.41 (ABq, J ) 18.4 Hz, ∆V ) 37.3 Hz, 2H), 2.86 (m,
1H), 1.99 (br s, 1H), 1.70-1.54 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 168.6, 136.9, 132.6, 128.7, 128.6, 127.7, 118.2, 80.1,
62.5, 58.8, 58.4, 49.8, 29.9, 21.2; IR (neat) 3350, 2931, 2870, 1736
cm-1; MS (DCI/IC4) m/z 276 (MH+, 100), 275 (3), 91 (3); HRMS
calcd for C25H44NOSi (MH+) 402.3192, found 402.3203; [R]23
+34.06 (c 2.63, CH2Cl2).
)
D
(2S,6R)-3-(1-Benzyl-6-methyl-1,2,5,6-tetrahydropyridin-2-yl)-
propan-1-ol (22). A solution of tetrabutylamonium fluoride (1.34
mL of a 1.0 M solution in THF, 1.34 mmol) was added to a stirring
solution of 21 (0.540 g, 1.34 mmol) in THF (15 mL). After stirring
for 5 h at rt, NaHCO3 (saturated aqueous 20 mL) was added. The
aqueous layer was extracted with CH2Cl2 (3 × 20 mL), dried (Na2-
SO4), and concentrated to afford crude product (0.906 g) as yellow
oil. Flash chromatography (1:1 hexanes/ethyl acetate, 2% triethy-
lamine) gave alcohol 22 (0.325 g, 98%) as clear oil: 1H NMR (300
MHz, CDCl3) δ 7.38-7.23 (m, 5H), 5.76 (dm, J ) 10.1 Hz, 1H),
5.45 (br dm, J ) 10.1 Hz, 1H), 3.92 (ABq, J ) 15.4 Hz, ∆V )
42.2 Hz, 2H), 3.52 (m, 2H), 3.24 (br m, 1H), 2.94 (m, 1H), 2.10
(dm, J ) 17.1 Hz, 1H), 1.94 (dm, J ) 17.6 Hz, 1H), 1.83-1.49
(m, 4H), 1.25 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
137.9, 129.3, 128.8, 128.2, 127.1 124.5, 62.7, 58.0, 54.1, 50.9, 31.8,
31.5, 28.5, 21.2; IR (CH2Cl2) 3613, 3058, 2985 cm-1; MS (DCI/
NH3) m/z 246 (MH+, 100), 244 (3), 191 (7), 186 (11), 174 (17);
HRMS calcd for C16H24NO (MH+) 246.1858, found 246.1867;
calcd for C16H22NO3 (MH+) 276.1600, found 276.1598; [R]21
+2.1 (c 0.34, CH2Cl2).
)
D
[R]22 ) -21.1 (c 1.51, CH2Cl2).
D
(2S,6R)-N-Phenylmethyl-6-[[(2-triisopropylsilyl)oxy]carbonyl]-
2-[[(3-triisopropylsilyl)oxy]propyl]-1-2,5,6-tetrahydropyridine
(20). Triisopropylsilyltriflate (0.0295 mL, 0.110 mmol) was added
to a benzene (1 mL) solution of morpholinone 18 (15.1 mg, 0.0548
mmol) and triethylamine (0.0382 mL, 0.274 mmol) in a pressure
vessel (Schlenk). The resulting mixture was cooled to -78 °C. The
vessel was then evacuated and sealed. It was then slowly warmed
to rt under vacuum. The process was repeated two more times.
After the pressure vessel was sealed, the reaction mixture was heated
to 200 °C for 18 h. After cooling to rt, the resulting suspension
was filtered through basic Al2O3 (activity 1, 9:1 hexanes/ethyl
acetate) and concentrated to give crude product (18.4 mg) as a pale
yellow oil. Flash chromatography (3:1 hexanes/ethyl acetate, 2%
(2S,6R)-3-(1-Benzyl-6-methyl-1,2,5,6-tetrahydropyridin-2-yl)-
propionaldehyde (23). A solution of DMSO (0.116 mL, 1.63
mmol) in CH2Cl2 (2 mL) was added to a stirred solution of oxalyl
chloride (0.0853 mL, 0.978 mmol) in CH2Cl2 (5 mL) at -78 °C
over 5 min. A solution of alcohol 22 (80.0 mg, 0.326 mmol) in
CH2Cl2 (4 mL) was added, and the resulting mixture was stirred
for 30 min at -78 °C. Triethylamine (0.273 mL, 1.96 mmol) in
CH2Cl2 (2 mL) was then added, and the resulting solution was
allowed to warm to 0 °C over 20 min. Aqueous K2CO3 (0.3 M, 10
mL) was added, and the aqueous layer was extracted with CHCl3
(3 × 10 mL). The combined organic extracts were washed with
H2O and brine, dried (K2CO3), and concentrated to give crude
product (178 mg) as dark yellow oil. Flash chromatography (5:1
J. Org. Chem, Vol. 72, No. 23, 2007 8795