7998
K. Sparrow et al. / Tetrahedron 67 (2011) 7989e7999
(br), H-7), 5.62 (1H, s (br), H-9), 5.91 (1H, d (br), J¼9.6 Hz, H-8),
7.15e7.20 (3H, m, Ph), 7.24e7.28 (2H, m, Ph). dC (100 MHz, CDCl3)
20.5 (CH2), 21.1 (CH2), 22.1 (CH2), 26.7 (CH2), 27.9 (CH3, tBu), 40.1 (C,
C-6), 43.1 (CH, C-2), 48.6 (CH2, CH2Ph), 51.0 (CH, C-7), 51.5 (CH3,
eOCH3), 70.6 (CH, C-1), 80.1 (C, tBu), 124.3 (CH, C-9), 126.3 (CH, Ph),
126.4 (CH, Ph), 127.9 (CH, Ph), 130.9 (CH, C-8), 140.3 (C, Ph), 156.6 (C,
NC]O), 177.2 (C, eCO2CH3). IR: nmax(film)/cmꢀ1; 3468 (OeH), 3032
(C]C), 2932,1741 (C]O),1663 (C]O),1450,1404. MS m/z (EIþ) 452
(MNaþ, 100), 430 (MHþ, 23), 330 (25), 223 (85), 173 (5), 152 (34).
HRMS (EIþ) found (MNaþ): 452.2396. Calculated: 452.2407.
(CH2, -CH2Ph), 59.3 (C, C-9), 65.9 (CH, C-4), 121.6 (CH, C-6), 127.3 (CH,
p-Ph), 128.4 (CH, Ph), 129.1 (CH, Ph), 132.5 (CH, C-5), 138.5 (C, Ph),
171.6 (C, eCO2CH3), 212.3 (C, C-13); IR: nmax (film)/cmꢀ1; 3025 (C]C),
2982, 2914, 2844, 1738 (C]O), 1711, 1649, 1603, 1495, 1444. MS m/z
(EIþ) 362 (MNaþ, 3), 340 (100), 308 (3), 221 (10), 189 (3), 120 (2).
HRMS (EIþ) found (MHþ): 340.1902. Calculated: 340.1907.
3.1.29. (1R,4R,9S,13S)-Methyl 3-benzyl-13-hydroxy-3-azatricyclotr-
idec[8.3.1.04,9]-5-ene-1-carboxylate 33. To a solution of ketone 31
(0.26 g, 0.77 mmol) in MeOH (10 mL) at 0 ꢁC was added NaBH4 flakes
(100 mg, 2.6 mmol). After 1 h, a further portion of NaBH4 (100 mg,
2.6 mmol) was added. After another hour, a third portion of NaBH4
(100 mg, 2.6 mmol) was added and the reaction mixture was warmed
to 13 ꢁC. Thereactionwasquenched with1:1 satdNH4Cl/NaCl (30 mL)
and the aqueous phase extracted with DCM (4ꢂ40 mL). The combine
organic extracts were dried over MgSO4, concentrated in vacuo and
the crude product purified by flash column chromatography (9:1 n-
hexanes/EtOAc) to afford the title compound as a light-blue oil that
darkened on storage (0.17 g, 64%). The intensely blue-coloured im-
purity was not detectable by NMR spectroscopy.
3.1.27. (2S,6S,7R)-Methyl 7-(benzyl(tert-butoxycarbonyl)amino)-1-
oxospiro[5.5]undec-8-ene-2-carboxylate 32. DesseMartin period-
inane (4.6 g, 10.9 mmol) was suspended in dry DCM (60 mL) under
a N2 atmosphere at 0 ꢁC. Dry pyridine (0.5 mL, 6.2 mmol) was
added, the mixture was warmed to room temperature and stirred
for 30 min. The homogenous solution was cooled to 0 ꢁC and a so-
lution of alcohol 30 (2.6 g, w5.2 mmol) in dry DCM (20 mL) was
added dropwise. After 2 h, the reaction was quenched with satd
NaHCO3 (40 mL), filtered through CeliteÒ and the organic layer was
separated. The aqueous layer was extracted with DCM (3ꢂ40 mL)
and the combined organic extracts dried over MgSO4. The filtrate
was concentrated in vacuo and purified by flash column chroma-
tography (9:1 n-hexanes/EtOAc) to afford the title compound as
½
a 2D0
ꢃ
þ7.0 (c 2.3, CHCl3), dH (400 MHz; CDCl3; Me4Si) 1.39 (1H, dt,
J¼13.2, 6.4 Hz, H-10A), 1.45e1.60 (3H, m, H-11A, H-8A, H-10B), 1.71
(1H, dd, J¼13.2, 6.4 Hz, H-12A), 1.77 (1H, dd, J¼14.0, 6.4 Hz, H-8B),
1.99 (1H, ddt, J¼13.2, 6.8, 1.6 Hz, H-12B), 1.98e2.06 (1H, m, H-7A),
2.43e2.51 (1H, m, H-7B), 2.67 (1H, d, J¼12.0 Hz, H-2), 2.74e2.87
(1H, m, H-11B), 3.08 (1H, dd, J¼12.0, 1.2 Hz, H-2), 3.33e3.35 (1H, m,
H-4), 3.61 (3H, s, eOCH3), 3.76 (1H, d, J¼13.2 Hz, eCH2Ph), 3.80 (1H,
s, H-13), 3.81 (1H, d, J¼13.2 Hz, eCH2Ph), 5.90 (1H, dq, J¼10.4,
3.0 Hz, H-6), 6.10 (1H, dd, J¼10.4, 1.6 Hz, H-5), 7.22e7.26 (1H, m, p-
Ph), 7.28e7.36 (4H, m, Ph). dC (100 MHz, CDCl3) 22.4 (CH2, C-11),
26.2 (CH2, C-7), 35.8 (CH2, C-12), 36.0 (CH2, C-8), 37.5 (C, C-9), 42.8
(CH2, C-10), 49.5 (CH2, C-2), 51.2 (C, C-1), 52.1 (CH3, eOCH3), 59.4
(CH2, eCH2Ph), 61.6 (CH, C-4), 79.8 (CH, C-13), 125.4 (CH, C-6), 128.0
(CH, C-5), 129.3 (CH, Ph), 130.1 (CH, Ph), 132.7 (CH, C-5), 140.6 (C,
Ph), 177.6 (C, C]O); IR: nmax (film)/cmꢀ1; 3550 (OeH), 3025 (CeH,
Ph), 2915 (CeH), 2844, 1729 (C]O), 1451, 1433. HRMS (EIþ) found
(MHþ): 342.2061. Calculated: 342.2064.
a colourless oil (1.5 g, 67%). ½a D20
ꢃ
ꢀ81.8 (c 0.5, CHCl3); dH (400 MHz;
t
CDCl3; Me4Si) 1.20 (9H, s (br), Bu), 1.33e1.47 (1H, m), 1.57e1.68
(1H, m), 1.75e1.84 (1H, m), 1.92e2.04 (2H, m), 2.08e2.19 (3H, m),
2.20e2.32 (2H, m), 3.72 (3H, s, eOCH3), 4.22 (1H, dd, J¼5.4, 13.3 Hz,
H-2), 4.29 (2H, s (br), CH2Ph), 5.45 (1H, s (br), H-7), 5.54e5.57 (1H,
m, H-9), 5.86e5.91 (1H, m, H-8), 7.08e7.11 (2H, m, o-Ph), 7.15e7.19
(1H, m, p-Ph), 7.22e7.26 (2H, m, m-Ph). dC (100 MHz, CDCl3) 19.7
(CH2), 20.6 (CH2), 25.8 (CH2), 27.9 (CH3, tBu), 29.9 (CH2), 35.6 (CH2),
48.0 (CH2, CH2Ph), 51.6 (CH3, eOCH3), 51.7 (C, C-6), 52.1 (CH, C-7),
55.0 (CH, C-2), 80.5 (C, tBu), 123.4 (CH, C-9), 126.1 (CH, o-Ph), 127.7
(CH ꢂ2, Ph), 130.9 (CH, C-8), 140.1 (C, Ph), 156.5 (C, NC]O), 171.3 (C,
eCO2CH3), 209.3 (CH, C]O). IR: nmax (film)/cmꢀ1; 3021 (C]C),
2980, 2947, 2924, 2868, 1747 (C]O), 1707, 1676, 1668 (C]O), 1607,
1500,1481,1448,1435,1402. MS m/z (EIþ) 450 (MNaþ, 90), 428 (26),
372 (40), 328 (100), 296 (22), 221 (16), 189 (3). HRMS (EIþ) found
(MNaþ): 450.2242. Calculated: 450.2251.
3.1.30. (þ)-Ester 34. Pd(OAc)2 (15 mg, 67
mmol) was added to a so-
lution of alcohol 33 (98 mg, 287 mol) in DMSO (8 mL) and heated at
m
circa 50 ꢁC under an O2 atmosphere overnight (18 h). H2O (80 mL)
was added and the aqueous layer extracted with Et2O (4ꢂ80 mL).
The combined organic extracts were washed with satd NaCl (20 mL),
dried over MgSO4 and concentrated in vacuo. The crude material was
purified by flash column chromatography (4:1 n-hexanes/EtOAc) to
3.1.28. (1R,4R,9S)-Methyl-3-benzyl-13-oxo-3-azatricyclotridec
[8.3.1.04,9]-5-ene-1-carboxylate 31. To (6S,7R)-methyl 7-(tert-butox-
ycarbonyl(benzyl)amino)-1-oxospiro[5.5]undec-8-ene-2-carboxylat-
e 32 (59 mg, 0.14 mmol) dissolved in DCM (1 mL) at 0 ꢁC was added
TFA (1 mL). The reaction was stirred for 1 h then concentrated in
vacuo (40 ꢁC) to afford an amber gum that was used in the next step
without further purification. The crude TFA salt was dissolved in
methanol (1 mL). Formalin (0.1 mL, 37 % w/w, 1.4 mmol) was added
followed by K2CO3 (48 mg, 0.35 mmol). TLC monitoring showed that
the reaction was complete within 5 min. The reaction mixture was
diluted with DCM (20 mL) and H2O (5 mL), the organic layer was
separated and the aqueous layer extracted with DCM (3ꢂ5 mL). The
combined organic fractions were dried over MgSO4 and concentrated
in vacuo to afford the title compound as a colourless oil that solidified
afford 34 as a colourless oil (95 mg, 97%). ½a D20
þ62.3 (c 1.9, CHCl3); dH
ꢃ
(400 MHz; CDCl3; Me4Si) 1.45e1.63 (3H, m, H-12, H-13, H14),
1.83e1.86 (1H, m, H-12), 1.99 (1H, dd, J¼14.0, 5.6 Hz, H-14),
2.18e2.24 (1H, m, H-7), 2.25e2.31 (1H, m, H-7), 2.49e2.61 (1H, m,
H-13), 2.79 (1H, d, J¼11.2 Hz, H-11), 2.89 (1H, s, H-9), 2.91 (1H, dd,
J¼11.6, 1.6 Hz, H-11), 3.64 (2H, s, eCH2Ph), 3.66 (3H, s, eOCH3), 4.25
(1H, s, H-2), 4.41 (1H, d, J¼5.6 Hz, H-4), 5.64e5.66 (1H, m, H-6),
6.04e6.08 (1H, m, H-5), 7.23e7.27 (1H, m, p-Ph), 7.31e7.32 (4H, m,
Ph). dC (100 MHz, CDCl3) 20.2 (CH2, C-13), 32.7 (CH2, C-14), 32.9 (CH2,
C-12), 41.1 (C, C-8), 43.9 (CH2, C-7), 48.9 (C, C-1), 51.9 (CH3, eOCH3),
52.2 (CH2, C-11), 59.9 (CH2, eCH2Ph), 68.3 (CH, C-9), 69.7 (CH, C-4),
85.8 (CH, C-2), 127.0 (CH, p-Ph), 128.3 (CH, Ph), 128.6 (CH, Ph), 130.9
(CH, C-6),131.8 (CH, C-5),138.9 (C, Ph),175.8 (C, C]O). IR: nmax (film)/
cmꢀ1; 3031 (CeH, Ph), 2928 (CeH), 2862, 1729 (C]O), 1454, 1434.
HRMS (EIþ) found (MHþ): 340.1914. Calculated: 340.1907.
upon refrigeration (31 mg, 65%). Mp¼75e80 ꢁC (CH2Cl2); ½a D20
þ7.7 (c
ꢃ
0.7, CHCl3); dH (400 MHz; CDCl3; Me4Si) 1.18e1.26 (1H, m, H-8),
1.53e1.61 (1H, m, H-11), 1.71 (1H, ddd, J¼5.2, 12.0, 13.2 Hz, H-10),
1.89e1.94 (1H, m, H-7), 1.96 (1H, q, J¼6.8 Hz, H-8), 2.09e2.20 (2H, H-
11, H-12), 2.44e2.56 (2H, m, H-8, H-12), 2.90 (1H, dd, J¼1.0,11.2 Hz, H-
2), 2.98e3.11 (1H, m, H-11), 3.38 (1H, dd, J¼1.6,11.6 Hz, H-2), 3.69 (3H,
s, eCO2CH3), 3.71 (1H, d, J¼13.2 Hz, eCH2Ph), 3.71 (1H, s, H-4), 3.88
(1H, d, J¼12.8 Hz, eCH2Ph), 5.87 (1H, s, H-5), 5.88 (1H, t, J¼13.0 Hz, H-
6), 7.2e7.30 (1H, m, p-Ph), 7.33e7.40 (4H, m, Ph). dC (100 MHz, CDCl3)
21.4 (CH2, C-11), 23.4 (CH2, C-7), 30.3 (CH2, C-8), 38.0 (CH2, C-12), 43.7
(CH2, C-10), 48.6 (C, C-1), 52.1 (CH3, CO2CH3), 55.3 (CH2, C-2), 57.6
3.1.31. (þ)-Alcohol 2. Pd/C 10% (20 mg) was added to a solution of
ester 34 (47 mg, 0.14 mmol) in 1:1 MeOH/EtOAc (10 mL) with cHCl (5
drops). The slurry was heated at circa 50 ꢁC with vigorous stirring
under a H2 atmosphere for 4 h. The mixture was filtered through
CeliteÓ and the solids were washed with ethyl acetate. The filtrate