M. Brambilla et al. / Tetrahedron 70 (2014) 204e211
209
CDCl3) 1.30e1.60 (2H, m, CH2), 1.63e1.95 (4H, m, CH2), 2.36e2.54
(2H, m, C(1)H, C(3)HA), 2.58e2.72 (1H, m, C(5)HA), 2.90e3.01 (1H,
m, C(5)HB), 3.12e3.27 (1H, m, C(3)HB), 3.36 (1H, br s, OH),
3.40e3.55 (1H, m, C(7a)H), 3.60e3.71 (2H, m, CH2OH); dC (100 MHz,
CDCl3) 25.9, 26.6, 27.3 (C(2), C(6), C(7)), 43.8 (C(1)), 53.9, 55.5
(C(3), C(5)), 63.6 (CH2OH), 66.5 (C(7a)); m/z (ESIþ) 142 ([MþH]þ,
100%); HRMS (ESIþ) C8H16NOþ ([MþH]þ) requires 142.1226; found
142.1229.
Method B: DIBAL-H (1.0 M in THF, 7.0 mL, 7.0 mmol) was added
to a stirred solution of 23$HOAc (150 mg, 0.7 mmol) in THF (15 mL)
at 0 ꢁC. The resultant mixture was allowed to warm to rt and stirred
at rt for 18 h. 2.0 M aq NaOH (3.5 mL, 7.00 mmol) was then added
and the resultant mixture was heated at reflux for 1 h. The reaction
mixture was filtered through CeliteÒ (eluent THF), then dried and
concentrated in vacuo. Purification via ion exchange chromatog-
raphy on Dowex-50WX8 resin (hydrogen form, 100e200 mesh,
eluent 18 M aq NH4OH) gave 1 as a pale yellow oil (11 mg, 17%,
>99:1 dr, w90% purity).
350 ([MþH]þ, 100%); HRMS (ESIþ) C20H32NOþ4 ([MþH]þ) requires
350.2326; found 350.2321.
4.12. (1R,7aS)-1-(tert-Butoxycarbonyl)octahydropyrrolizin-4-
ium acetate 28$HOAc
Step 1: NaIO4 (220 mg, 1.03 mmol) was added to a solution of 26
(150 mg, 0.34 mmol, >99:1 dr) in MeOH (10 mL) and the resultant
suspension was stirred at rt for 1 h. The reaction mixture was then
filtered through a short plug of CeliteÒ (eluent MeOH) then con-
centrated in vacuo. The residue was dissolved in Et2O (20 mL) and
the resultant solution was filtered through a short plug of CeliteÒ
(eluent Et2O) and then concentrated in vacuo.
Step 2: Pd(OH)2/C (24 mg) was added to a stirred solution of the
residue in degassed MeOH (5 mL) and AcOH (0.25 mL) and the
resultant suspension was stirred at rt for 24 h under an atmosphere
of H2 (5 atm). The reaction mixture was then filtered through
a short plug of CeliteÒ (eluent MeOH) and concentrated in vacuo to
25
give 28$HOAc as pale yellow oil (350 mg, quant, >99:1 dr); [a]
D
4.10. tert-Butyl (1R,3R,4S,7S,
a
S)-3,4-dihydroxy-7-[N-benzyl-
ꢀ11.9 (c 0.7, CHCl3); nmax (ATR) 3401 (NeH), 1719 (C]O); dH
(400 MHz, CDCl3) 1.39 (9H, s, CMe3), 1.72e1.85 (1H, m, CH2),
1.88e1.96 (4H, m, CH2, MeCO2ꢀ), 1.99e2.08 (1H, m, CH2), 2.15e2.28
(3H, m, CH2), 2.65 (1H, app q, J 8.1, C(1)H), 2.69e2.86 (2H, m, C(3)HA,
C(5)HA), 3.52e3.64 (1H, m, C(3)HB), 3.81e3.90 (1H, m, C(5)HB),
4.25e4.34 (1H, m, C(7a)H); dC (100 MHz, CDCl3) 21.9 ðMeCO2ꢀÞ,
24.6, 29.2, 30.3 (C(2), C(6), C(7)), 27.9 (CMe3), 50.1 (C(1)), 53.9, 54.5
N-( -methylbenzyl)amino]cycloheptanecarboxylate 26
a
OsO4 (125 mg, 0.49 mmol) was added to a stirred solution of 20
(150 mg, 0.44 mmol) and TMEDA (95 L, 0.62 mmol) in CH2Cl2
m
(10 mL) at ꢀ78 ꢁC. The reaction mixture was stirred at ꢀ78 ꢁC for 1 h
and then allowed to warm to rt over 15 min. The residue was then
diluted with CH2Cl2 (40 mL) and tris(hydroxymethyl)phosphine
(5.5 g, 45 mmol), Et3N (1.2 mL, 8.8 mmol) and excess silica gel were
added sequentially. The resultant mixture was left to stir at rt for
48 h, then filtered through a short plug of silica gel (eluent CH2Cl2)
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/EtOAc, 4:1) gave 26 as a white
t
(C(3), C(5)), 67.9 (C(7a)), 82.3 (CMe3), 169.7 (CO2 Bu), 176.6
ðMeCO2ꢀÞ; þ m/z (ESIþ) 212 ([MþH]þ, 100%); HRMS (ESIþ)
C
12H22NO2 ([MþH]þ) requires 212.1645; found 212.1646.
4.13. (1R,2S,5S,6S,aS)-2-[N-Benzyl-N-(a-methylbenzyl)-
amino]-5-hydroxy-7-oxabicyclo[4.2.1]nonan-8-one 29
solid (100 mg, 52%, >99:1 dr); mp: 102e104 ꢁC; [
CHCl3); nmax (ATR) 3401 (OeH), 1720 (C]O); dH (400 MHz,
a
]
25 ꢀ56.3 (c 1.00,
D
HBF4 (48% in H2O, 320 mL, 2.50 mmol) was added to a stirred
CDCl3) 1.28 (3H, d, J 6.8, C(
a
)Me),1.43 (9H, s, CMe3),1.55e1.70 (2H, m,
solution of 20 (200 mg, 0.50 mmol, >99:1 dr) in CH2Cl2 (1.3 mL).
After 5 min m-CPBA (70% in H2O, 240 mg, 1.00 mmol) was added
and the resultant mixture was left to stir at rt for 48 h. CH2Cl2
(20 mL), satd aq Na2SO3 (10 mL) and satd aq NaHCO3 (10 mL) were
added sequentially and the aqueous layer was extracted with
CH2Cl2 (3ꢂ15 mL). The combined organic extracts were then dried
and concentrated in vacuo to give 29 in >95:5 dr. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/EtOAc, 4:1)
C(2)HA, C(5)HA),1.70e1.85 (2H, m, C(2)HB, C(5)HB),1.82 (1H, app dt, J
9.8, 1.2, C(6)HA), 2.06e2.23 (1H, m, C(6)HB), 2.56 (1H, app dt, J 7.6,
4.3, C(1)H), 3.13 (1H, app dt, J 11.1, 4.3, C(7)H), 3.84 (1H, d, J 14.7,
NCHAHBPh), 3.83e3.96 (3H, m, C(3)H, C(4)H, C(
14.7, NCHAHBPh), 7.18e7.47 (10H, m, Ph); dC (100 MHz, CDCl3) 14.5
(C( )Me), 24.5 (C(6)), 28.1 (CMe3), 29.7 (C(5)), 32.2 (C(2)), 46.4 (C(1)),
51.1 (NCH2Ph), 57.5 (C( )), 58.7 (C(7)), 71.3 (C(3)), 74.1 (C(4)), 80.4
a)H), 4.05 (1H, d, J
a
a
(CMe3),126.4,126.6,127.8,127.9,128.0,128.4 (o,m,p-Ph),142.2,144.3
gave 29 as a white solid (120 mg, 74%, >99:1 dr); mp 39e40 ꢁC;
t
25
(i-Ph), 174.7 (CO2 Bu); m/z (ESIþ) 440 ([MþH]þ, 100%); HRMS (ESIþ)
[a
]
ꢀ30.2 (c 1.0, CHCl3); nmax (ATR) 3433 (OeH), 1772 (C]O);
D
þ
C27H37NNaO4 ([MþNa]þ) requires 462.2615; found 462.2592.
dH (400 MHz, CDCl3) 1.27 (3H, d, J 6.7, C(a)Me), 1.31e1.45 (1H, m,
C(9)HA), 1.60e1.80 (3H, m, C(4)HA, C(3)HA, OH), 1.93e2.02 (1H, m,
C(3)HB), 2.10e2.25 (2H, m, C(4)HB, C(9)HB), 2.00e2.62 (1H, app d, J
8.8, C(1)H), 2.86 (1H, app dt, J 10.3, 2.8, C(2)H), 3.83 (1H, d, J
14.6, NCHAHBPh), 4.01 (1H, d, J 14.6, NCHAHBPh), 3.94e4.00 (1H, m,
4.11. tert-Butyl (1R,3R,4S,7S,
benzyl)amino]cycloheptanecarboxylate 27
aS)-3,4-dihydroxy-7-[N-(a-methyl-
CAN (150 mg, 0.22 mmol) was added to a stirred solution of 26
(60 mg, 0.13 mmol, >99:1 dr) in MeCN/H2O (5:1, 2.7 mL) and the
resultant mixture was stirred at rt for 2 h. Then satd aq NaHCO3
(5 mL) was added and the reaction mixture was left to stir at rt for
10 min. The resultant mixture was then extracted with EtOAc
(3ꢂ10 mL) and the combined organic extracts were dried and
C(5)H), 4.04 (1H, q, J 6.7, C(
7.20e7.60 (10H, m, Ph); dC (100 MHz, CDCl3) 15.4 (C(
(C(3)), 28.0 (C(4)), 31.5 (C(9)), 43.6 (C(1)), 51.0 (NCH2Ph), 57.4 (C(
a
)H), 4.49 (1H, app q, J 8.1, C(6)H),
)Me), 25.7
)),
a
a
62.1 (C(2)), 71.8 (C(5)), 81.9 (C(6)), 126.6, 126.8, 127.6, 128.2, 128.4
(o,m,p-Ph), 142.0, 144.0 (i-Ph), 178.5 (C(8)); m/z (ESIþ) 366 ([MþH]þ,
þ
100%); HRMS (ESIþ) C23H27NNaO3 ([MþNa]þ) requires 388.1883;
concentrated in vacuo to give 27 as a white solid (42 mg, 97%, >99:1
found 388.1871.
25
dr); mp: 106e108 ꢁC; [
a]
ꢀ26.8 (c 1.2, CHCl3); nmax (ATR)
D
3397 (OeH),1715 (C]O); dH (500 MHz, CDCl3) 1.28 (3H, d, J 6.6, C(
a)
4.14. (1R,2S,5S,6S,aS)-2-[N-(a-Methylbenzyl)amino]-5-
Me), 1.30e1.38 (1H, m, C(6)HA), 1.58 (9H, s, CMe3), 1.52e1.57 (1H, m,
C(5)HA), 1.56e1.66 (1H, m, C(5)HB), 1.83e1.92 (2H, m, C(2)HA, C(6)
HB), 1.93e2.00 (1H, m, C(2)HB), 3.04e3.10 (2H, m, C(1)H, C(7)H),
hydroxy-7-oxabicyclo[4.2.1]nonan-8-one 30
CAN (620 mg, 1.13 mmol) was added to a stirred solution of 29
(200 mg, 0.54 mmol, >99:1 dr) in MeCN/H2O (5:1, 9 mL) and the
resultant mixture was stirred at rt for 2 h. Satd aq NaHCO3 (10 mL)
was then added and the reaction mixture was left to stir at rt for
10 min. The resultant mixture was extracted with EtOAc (3ꢂ20 mL)
and the combined organic extracts were dried and concentrated in
3.70 (1H, app td, J 9.8, 3.5, C(4)H), 3.83 (1H, q, J 6.6, C(
app td, J 7.3, 3.5, C(3)H), 7.20e7.33 (5H, m, Ph); dC (125 MHz, CDCl3)
24.0 (C( )Me), 27.9 (C(5)), 28.2 (CMe3), 28.9 (C(2)), 29.4 (C(6)), 42.2
(C(1)), 55.4 (C( )), 55.8 (C(7)), 70.4 (C(3)), 74.6 (C(4)), 80.5 (CMe3),
126.5,126.6,128.3 (o,m,p-Ph),146.4 (i-Ph),174.1 (CO2 Bu); m/z (ESIþ)
a)H), 4.06 (1H,
a
a
t