P. Singh et al. / Tetrahedron 70 (2014) 1363e1374
1371
compound 20 (165 mg, 32% over four steps). Yellowish liquid, eluent
chromatography: EtOAc/Hexane (13.5/26.5, v/v). ½a D28
ꢃ
þ1.4 (c 0.83,
for column chromatography: EtOAc/Hexane (12/38, v/v); ½a D28
ꢃ
ꢀ18.5
MeOH); Rf 0.3 (1/1 EtOAc/Hexane); IR (neat, cmꢀ1) 3418, 2936,
(c 0.39, CHCl3); Rf 0.4 (3:7 EtOAc/Hexane); IR (neat, cmꢀ1) 2364, 1742,
2364, 1654, 1433, 1057, 745; 1H NMR (300 MHz, CDCl3)
d 7.33e7.24
1617, 1225, 1098, 769; 1H NMR (300 MHz, CDCl3)
d
7.25e7.11 (15H, m,
(5H, m, ArH), 4.62 (1H, d, J¼11.8 Hz, OCH2Ph), 4.51e4.47 (2H, m,
OCH2Ph, CHAHBOH), 3.98 (1H, d, J¼12 Hz, CHAHBOH), 3.75 (1H, t,
J¼8.2 Hz, NCHAHB), 3.64e3.57 (2H, m, NCHAHB), 2.9e2.82 (1H, m,
CHN), 2.30 (1H, br s, OH), 1.96e1.85 (2H, m, CH2CHOBn), 1.66e1.53
(2H, m, CH2CH2NBoc), 1.45 (9H, s, CMe3); 13C NMR (50 MHz, CDCl3)
ArH), 5.45e5.44 (1H, m, CHOAc), 5.20 (1H, t, J¼6.3 Hz, CHOAc),
4.49e4.46 (2H, m, OCH2Ph), 4.39e4.32 (2H, m, OCH2Ph), 4.29e4.23
(2H, m, OCH2Ph), 3.92 (1H, d, J¼7.9 Hz, CHOBn), 3.70 (1H, t, J¼2.8 Hz,
CHOBn), 3.50 (1H, br s, CHOBn), 2.95e2.91 (2H, m, CHN, NCHAHB),
2.68 (m, 1H, NCHAHB), 2.58 (m, 1H, NCHAHB), 2.34 (d, J¼9.4 Hz, 1H,
NCHAHB), 1.95 (3H, s, CH3CO), 1.92 (3H, s, CH3CO); 13C NMR (75 MHz,
d
156.4,138.6,128.3,127.4, 79.9, 71.5, 70.1, 60.7, 55.7, 39.6, 28.4, 25.3,
þ
19.4; (ESI-MS) m/z 322 [MþH]ꢄ
; HRMS (DART): calcd for
CDCl3)
d
170.3, 170.1, 138.25, 138.23, 137.9, 128.4, 128.3, 127.9, 127.8,
C
18H28NO4 [MþH]ꢄþ 322.20183, measured 322.20179.
127.7, 127.6, 74.2, 74.0, 72.7, 72.2, 71.5, 71.46, 71.3, 70.2, 63.1, 58.9, 51.0,
20.6; (ESI-MS) m/z 560 [MþH]ꢄþ; EI-HRMS: calcd for C33H38NO7
[MþH]ꢄþ: 560.26483, measured 560.26373.
4.1.28. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((S)-1-hydroxyallyl)piper-
idine-1-carboxylate: 29. To a solution of 28 (180 mg, 0.56 mmol) in
anhydrous CH2Cl2 (15 mL), under a nitrogen atmosphere was added
DesseMartin periodinane (356.28 mg, 0.84 mmol) at 0 ꢁC and the
reaction mixture was allowed to stir at ambient temperature for
30 min. Then, the reaction was quenched with aqueous solution of
saturated Na2S2O3 (10 mL), the organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with brine (15 mL), dried over Na2SO4, and
concentrated under vacuo to obtain the aldehyde, which was used
as such for the next step without purification. To a solution of al-
dehyde in dry THF, under N2 atmosphere at ꢀ78 ꢁC, vinyl magne-
sium bromide (1 M solution in THF, 1.68 mL) was added and
allowed to stir for one hour at same temperature. After completion
of reaction, it was quenched with saturated solution of NH4Cl, and
extracted with ethyl acetate (10 mLꢂ3). The combined organic
layer was washed with brine, dried over anhydrous Na2SO4, and
concentrated under vacuo to a colorless oil, which on column
chromatographic purification gave the pure compound 29 (color-
less oil, 109 mg, 56.2% in two steps). Eluent for column chroma-
4.1.25. (1S,2R,6S,7R,8S,8aS)-Octahydroindolizine-1,2,6,7,8-pentaol:
26. To a solution of compound 25 (50 mg, 0.11 mmol) in MeOH
(1 mL) was added catalytic amount of PdCl2. The mixture was
stirred at rt under an atmosphere of H2 (balloon) for 3 h. The
mixture was filtered through a Celite pad and the filtrates were
evaporated in vacuo, then the residue was dissolved in water (1 mL)
and applied to a column of Amberlyst IRA-100 basic ion-exchange
resin. Elution with water (30 mL) followed by evaporation of the
eluent in vacuo gave the title product 26 (18.2 mg, 85%) as a color-
less foam. IR (neat, cmꢀ1) 3600e3200; 1H NMR (300 MHz, D2O)
d
4.38e4.32 (1H, m, CHOH), 4.2e4.18 (1H, m, CHOH), 4.06 (1H, dd,
J¼10.3, 3.3 Hz, CHOH), 3.95 (1H, t, J¼3.3 Hz, CHOH), 3.89e3.88 (1H,
m, CHOH), 2.88 (m, 1H), 2.84 (1H, m, CHN), 2.60e2.54 (1H, m,
NCHAHB), 2.44 (1H, d, J¼1.6 Hz, NCHAHB), 2.40 (1H, d, J¼1.6 Hz,
NCHAHB), 2.33 (1H, dd, J¼10.2, 3.7 Hz, NCHAHB); 13C NMR (75 MHz,
D2O)
d 70.6, 70.1, 69.6, 69.2, 65.3, 65.1, 59.9, 51.9; (ESI-MS) m/z 206
[MþH]ꢄþ; EI-HRMS: calcd for C8H16NO5 [MþH]ꢄþ: 206.10285,
measured 206.10315.
tography: EtOAc/Hexane (7/43, v/v); ½a D28
ꢃ
þ17.5 (c 5.10, CHCl3); Rf
0.4 (1.2/7.8, EtOAc/Hexane); 1H NMR (300 MHz, CDCl3)
d
7.25e7.16
4.1.26. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((tert-butyl dimethylsily-
loxy)methyl)piperidine-1-carboxylate: 27. To a solution of com-
pound 1 (668.0 mg, 1.54 mmol) in methanol, catalytic amount of
triethyl amine (31.17 mg, 0.04 mL, 0.31 mmol) and 10% Pd/C was
added, and the solution was stirred under the pressure of H2 at-
mosphere in balloon at room temperature for 4 h. After completion
of the reaction, it was filtered through Celite, and the solvent was
evaporated under vacuum, which on column chromatographic
provided the pure product 27 (665 mg, 99%) as colorless oil. Eluent
(5H, m, ArH), 5.83 (1H, m, CH]CH2), 5.18 (1H, d, J¼17.3 Hz, CH2]
CH), 5.08 (1H, d, J¼10.3 Hz, CH2]CH), 4.55 (1H, d, J¼11.9 Hz,
OCH2Ph), 4.39 (1H, d, J¼11.9 Hz, OCH2Ph), 4.22 (2H, m, CHOH,
CHOBn), 4.00 (1H, br s, OH), 3.83 (1H, m, CHN), 2.64 (br s, 1H,
NCHAHB), 2.08 (br s, 1H, NCHAHB), 1.83e1.68 (m, 4H, CH2CHOBn,
CH2CH2NBoc), 1.35 (9H, s, CMe3); 13C NMR (300 MHz, CDCl3)
d
155.6, 138.9, 128.4, 128.1, 127.2, 116.8, 79.5, 71.1, 70.0, 57.2, 39.2,
28.4, 24.8, 19.4; (ESI-MS) m/z 370 [MþNa]ꢄþ; HRMS (ESI TOF (þ)):
calcd for C20H29NNaO4 [MþNa]ꢄþ: 370.19943, measured 370.19833.
for column chromatography: EtOAc/Hexane (2/48, v/v). ½a D28
þ2.2
ꢃ
(c 0.24, MeOH); Rf 0.5 (1/9 EtOAc/Hexane); IR (neat, cmꢀ1) 3441,
4.1.29. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((R)-1-hydroxyallyl)piper-
3020, 2364, 1676, 1216, 762, 670; 1H NMR (300 MHz, CDCl3)
idine-1-carboxylate: 30. Colorless oil (36.5 mg, 18.8%) eluent for
d
7.35e7.28 (5H, m, ArH), 4.64 (1H, d, J¼10.4 Hz, OCH2Ph),
column chromatography: EtOAc/Hexane (8/42, v/v); ½a D28
þ10.8 (c
ꢃ
4.52e4.35 (2H, m, OCH2Ph), 4.08 (1H, br s, CHAHBO), 3.74e3.68 (3H,
m, NCHAHB, CHN, CHAHBO), 2.79 (1H br s, NCHAHB), 1.87e1.68 (4H,
m, CH2CHOBn, CH2CH2NBoc), 1.47 (9H, s, CMe3), 0.89 (9H, s,
2.92, CHCl3); Rf 0.35 (1.2/7.8, EtOAc/Hexane); IR (neat, cmꢀ1) 3399,
2928, 2360, 1665, 1424, 1150, 769; 1H NMR (300 MHz, CDCl3)
d
7.35e7.24 (5H, m, ArH), 5.91e5.79 (1H, m, CH]CH2), 5.26 (1H, d,
SiCMe3), 0.06 (6H, s, SiMe2); 13C NMR (75 MHz, CDCl3)
d
155.5,
J¼17.2 Hz, CH2]CH), 5.15 (1H, d, J¼10.3 Hz, CH2]CH), 4.63 (1H, d,
J¼11.8 Hz, OCH2Ph), 4.47 (1H, d, J¼11.8 Hz, OCH2Ph), 4.29 (2H, m,
CHOBn, CHOH), 4.07 (1H, br s, CHN), 3.90 (1H, m, NCHAHB), 2.72
(1H, m, NCHAHB), 1.91e1.71 (4H, m, CH2CHOBn, CH2CH2NBoc), 1.53
138.8, 128.2, 127.3, 79.3, 71.2, 69.9, 61.1, 55.1, 39.1, 28.4, 25.8, 24.6,
19.4, 18.1, ꢀ5.4, ꢀ5.5; (ESI-MS) m/z 436 [MþH]ꢄþ, 336 [M-Boc];
þ
HRMS (DART): calcd for C24H42NO4Si [MþH]ꢄ 436.28831, mea-
sured 436.28781.
(9H, s, CMe3); 13C NMR (50 MHz, CDCl3)
d 155.6, 138.9, 138.4, 128.2,
127.2, 116.8, 79.5, 71.1, 70.0, 57.0, 39.2, 28.4, 24.8, 19.4; (ESI-MS) m/z
370 [MþNa]ꢄþ; HRMS (ESI TOF (þ)): calcd for C20H29NNaO4
[MþNa]ꢄþ: 370.19943, measured 370.19833.
4.1.27. (2S,3R)-tert-Butyl
3-(benzyloxy)-2-(hydroxymethyl)piperi-
dine-1-carboxylate: 28. To a cooled solution of 27 (890 mg,
2.04 mmol) in dry THF (10 mL), solution of TBAF (1.0 M in THF,
5.0 mL) was added, and allowed to stir for 30 min. After completion
of the reaction, mixture was concentrated in vacuo, the residue was
diluted with ethyl acetate. The combined organic layer was washed
with water followed by brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated under vacuum to colorless oil,
which on column chromatographic purification gave the pure
compound 28 as white gum (636 mg, 95%). Eluent for column
4.1.30. (2S,3R)-tert-Butyl 3-(benzyloxy)-2-((1R,2S)-1,2,3-
trihydroxypropyl)piperidine-1-carboxylate: 33. To a solution of 29
(146 mg, 0.42 mmol) in a 10:1 mixture of acetone/H2O (6.6 mL) was
added N-methylmorpholine N-oxide (98.51 mg, 0.84 mmol) and 4%
aqueous OsO4, (1.0 mL). The reaction mixture was stirred at room
temperature for 3 h. After addition of aqueous NaHSO3 solution
(1 mL), the mixture was stirred for an additional 1 h at room