H. Tamiaki et al. / Tetrahedron: Asymmetry 24 (2013) 967–972
971
(1H, dd, J = 12, 18 Hz, 3-CH), 6.53 (1H, m, 13-CH), 6.35 (1H, dd,
J = 2, 18 Hz, 31-CH trans to 3-C–H), 6.18 (1H, dd, J = 2, 12 Hz, 31-
CH cis to 3-C–H), 5.41/5.31 (1H, dd, J = 6, 16 Hz, 131-CH cis to 13-
C–H), 4.62/4.76 (1H, d, J = 16 Hz, 131-CH trans to 13-C–H), 4.65
(1H, q, J = 7 Hz, 18-H), 4.46 (1H, m, 17-H), 3.85 (2H, q, J = 8 Hz, 8-
CH2), 3.63 (3H, s, 12-CH3), 3.57 (3H, s, 2-CH3), 3.57/3.43 (3H, s,
172-COOCH3), 3.42 (3H, s, 7-CH3), 2.81–2.74, 2.62–2.53, 2.45–
2.31, 2.25–2.17 (each 1H, m, 17-CH2CH2), 1.85 (3H, d, J = 7 Hz,
18-CH3), 1.76 (3H, t, J = 8 Hz, 81-CH3), À1.37, À3.22 (each 1H, s,
NH Â 2); MS (TOF) found: m/z 550.0. Calcd for C34H38N4O3: M+,
550.3. Please also see the spectroscopic data in the literature.12,13
The above diastereomeric mixture was separated by RP-HPLC to
afford (131R)-epimer (R)-2 at tR = 6.7 min and (131S)-epimer (S)-2
at 7.9 min. (R)-2: Vis (CH2Cl2) kmax = 653 (relative absorbance,
0.26), 599 (0.03), 544 (0.03), 502 (0.10), 402 nm (1.00); 1H NMR
(400 MHz, CDCl3) d = 9.88 (1H, s, 5-H), 9.65 (1H, s, 10-H), 8.91
(1H, s, 20-H), 8.23 (1H, dd, J = 12, 18 Hz, 3-CH), 6.56 (1H, d,
J = 6 Hz, 13-CH), 6.35 (1H, dd, J = 1, 18 Hz, 31-CH trans to 3-C–H),
6.18 (1H, dd, J = 1, 12 Hz, 31-CH cis to 3-C–H), 5.41 (1H, dd, J = 6,
16 Hz, 131-CH cis to 13-C–H), 4.65 (2H, q, J = 7.5 Hz, 18-H), 4.63
(1H, d, J = 16 Hz, 131-CH trans to 13-C–H), 4.47 (1H, d, J = 9 Hz,
17-H), 3.85 (2H, q, J = 7.5 Hz, 8-CH2), 3.63 (3H, s, 12-CH3), 3.571
(3H, s, 172-COOCH3), 3.565 (3H, s, 2-CH3), 3.42 (3H, s, 7-CH3),
2.78–2.71, 2.62–2.54, 2.37–2.31, 2.24–2.18 (each 1H, m, 17-
CH2CH2), 1.85 (3H, d, J = 7.5 Hz, 18-CH3), 1.77 (3H, t, J = 7.5 Hz,
81-CH3), À1.34, À3.20 (each 1H, s, NH Â 2); MS (TOF) found: m/z
56.7 l
mol, 33%) as a 1:2.3 mixture of (131R)- and (131S)-epimers:
Vis (CH2Cl2) kmax = 652 (relative absorbance, 0.28), 596 (0.03), 502
(0.09), 402 nm (1.00); 1H NMR (400 MHz, CDCl3) d (131R/S = 1/
2.3) = 9.88 (1H, s, 5-H), 9.63 (1H, s, 10-H), 8.93 (1H, s, 20-H), 8.23
(1H, dd, J = 12, 18 Hz, 3-CH), 6.35 (1H, d, J = 18 Hz, 31-CH trans to
3-C–H), 6.18 (1H, d, J = 12 Hz, 31-CH cis to 3-C–H), 5.07/5.03 (1H,
d, J = 16 Hz, 131-CH cis to 13-C–CH3), 4.84/4.94 (1H, d, J = 16 Hz,
131-CH trans to 13-C–CH3), 4.64 (1H, q, J = 7 Hz, 18-H), 4.43 (1H,
d, J = 9 Hz, 17-H), 3.86 (2H, q, J = 8 Hz, 8-CH2), 3.62 (3H, s, 12-
CH3), 3.59/3.38 (3H, s, 172-COOCH3), 3.57 (3H, s, 2-CH3), 3.42
(3H, s, 7-CH3), 2.75–2.71, 2.59–2.48, 2.41–2.33, 2.30–2.23 (each
1H, m, 17-CH2CH2), 2.30/2.20 (3H, s, 131-CH3), 1.87 (3H, d,
J = 7 Hz, 18-CH3), 1.78 (3H, t, J = 8 Hz, 81-CH3), À1.47, À3.24 (each
1H, s, NH Â 2); MS (TOF) found: m/z 565.8. Calcd for C35H41N4O3:
MH+, 565.3; HRMS (FAB) found: m/z 565.3176. Calcd for
C
35H41N4O3: MH+, 565.3179.
The above diastereomeric mixture was separated by RP-HPLC
to afford (131R)-epimer (R)-3 at tR = 6.7 min and (131S)-epimer
(S)-3 at 7.7 min. (R)-3: Vis (CH2Cl2) kmax = 653 (relative absor-
bance, 0.27), 597 (0.03), 502 (0.10), 402 nm (1.00); 1H NMR
(400 MHz, CDCl3) d = 9.88 (1H, s, 5-H), 9.64 (1H, s, 10-H), 8.91
(1H, s, 20-H), 8.25 (1H, dd, J = 12, 18 Hz, 3-CH), 6.35 (1H, dd,
J = 1.5, 18 Hz, 31-CH trans to 3-C–H), 6.18 (1H, dd, J = 1.5,
12 Hz, 31-CH cis to 3-C–H), 5.12 (1H, d, J = 16 Hz, 131-CH cis to
13-C–CH3), 4.90 (1H, d, J = 16 Hz, 131-CH trans to 13-C–CH3),
4.65 (2H, q, J = 7.5 Hz, 18-H), 4.44 (1H, d, J = 9 Hz, 17-H), 3.85
(2H, q, J = 7.5 Hz, 8-CH2), 3.65 (3H, s, 12-CH3), 3.58 (3H, s, 172-
COOCH3), 3.57 (3H, s, 2-CH3), 3.42 (3H, s, 7-CH3), 2.77–2.71,
2.36–2.22, (each 1H, m, 17-CH2), 2.63–2.57, 2.24–2.18 (each
1H, m, 171-CH2), 2.42 (3H, s, 131-CH3), 1.84 (3H, d, J = 7.5 Hz,
18-CH3), 1.76 (3H, t, J = 7.5 Hz, 81-CH3), À3.22 (1H, s, NH) [an-
other NH could not be observed.]; MS (TOF) found: m/z 564.5.
550.6. Calcd for
C
34H38N4O3: M+, 550.3. (S)-2: Vis (CH2Cl2)
kmax = 652 (relative absorbance, 0.27), 597 (0.03), 549 (0.01), 502
(0.10), 401 nm (1.00); 1H NMR (400 MHz, CDCl3) d = 9.88 (1H, s,
5-H), 9.65 (1H, s, 10-H), 8.91 (1H, s, 20-H), 8.24 (1H, dd, J = 12,
18 Hz, 3-CH), 6.52 (1H, d, J = 6 Hz, 13-CH), 6.35 (1H, dd, J = 2,
18 Hz, 31-CH trans to 3-C–H), 6.18 (1H, dd, J = 2, 12 Hz, 31-CH cis
to 3-C–H), 5.30 (1H, dd, J = 6, 16 Hz, 131-CH cis to 13-C–H), 4.75
(1H, d, J = 16 Hz, 131-CH trans to 13-C–H), 4.65 (1H, q, J = 7.5 Hz,
18-H), 4.45 (1H, d, J = 9 Hz, 17-H), 3.85 (2H, q, J = 7.5 Hz, 8-CH2),
3.63 (3H, s, 12-CH3), 3.57 (3H, s, 2-CH3), 3.421 (3H, s, 172-COOCH3),
3.418 (3H, s, 17-CH3), 2.81–2.74, 2.61–2.53, 2.45–2.36, 2.24–2.17
(each 1H, m, 17-CH2CH2), 1.86 (3H, d, J = 7.5 Hz, 18-CH3), 1.77
(3H, t, J = 7.5 Hz, 81-CH3), À1.37, À3.32 (each 1H, s, NH Â 2); MS
(TOF) found: m/z 550.6. Calcd for C34H38N4O3: M+, 550.3. Please
also see the spectroscopic data in the literature.15
Calcd for
565.3180. Calcd for
C
35H40N4O3: M+, 564.3; HRMS (FAB) found: m/z
C
35H41N4O3: MH+, 565.3179. (S)-3: Vis
(CH2Cl2) kmax = 652 (relative absorbance, 0.28), 597 (0.03), 503
(0.09), 402 nm (1.00); 1H NMR (400 MHz, CDCl3) d = 9.89 (1H,
s, 5-H), 9.64 (1H, s, 10-H), 8.91 (1H, s, 20-H), 8.24 (1H, dd,
J = 12, 18 Hz, 3-CH), 6.35 (1H, dd, J = 1.5, 18 Hz, 31-CH trans to
3-C–H), 6.18 (1H, dd, J = 1.5, 12 Hz, 31-CH cis to 3-C–H), 5.07
(1H, d, J = 16 Hz, 131-CH cis to 13-C–CH3), 4.99 (1H, d,
J = 16 Hz, 131-CH trans to 13-C–CH3), 4.64 (1H, q, J = 7.5 Hz, 18-
H), 4.45 (1H, d, J = 9 Hz, 17-H), 3.85 (2H, q, J = 7.5 Hz, 8-CH2),
3.65 (3H, s, 12-CH3), 3.57 (3H, s, 2-CH3), 3.42 (3H, s, 7-CH3),
3.38 (3H, s, 172-COOCH3), 2.80–2.72, 2.44–2.37, (each 1H, m,
17-CH2), 2.59–2.51, 2.23–2.15 (each 1H, m, 171-CH2), 2.32 (3H,
s, 131-CH3), 1.87 (3H, d, J = 7.5 Hz, 18-CH3), 1.76 (3H, t,
J = 7.5 Hz, 81-CH3), À1.17, À3.01 (each 1H, s, NH Â 2); MS (TOF)
Similar to the above synthesis, the reduction of 1a (54.0 mg,
98.5
l
mol) in THF (5 mL) with
mol) for 30 min gave a 1:3.4 mixture of (R)-2 and (S)-2
mol, 20%) and 1a (42.6 mg, 77.7 mol) was recov-
ered. The yield based on consumed 1a was 95%. Using 5 equiv of
L-selectride in THF (1 M, 100 lL,
100
l
(10.9 mg, 19.8
l
l
L
-
selectride, 1a was completely reduced to afford the same 1:3.4
mixture of (R)-2/(S)-2, while by-products bearing a 17-hydroxy-
propyl group were partially produced through further reduction
of the 172-COOMe to CH2OH.
found: m/z 564.6. Calcd for
(FAB) found: m/z 565.3179. Calcd for
C
35H40N4O3: M+, 564.3; HRMS
C
35H41N4O3: MH+,
565.3179.
4.2.2. Synthesis of methyl 131-deoxo-131-hydroxy-131-methyl-
pyropheophoride-a 3
4.2.3. Synthesis of methyl 131-deoxo-131-hydroxy-131-phenyl-
pyropheophoride-a 4
Ketone 1b (91.2 mg, 171
lmol) was dissolved in THF (40 mL) at
Similar to the synthesis of 3, the reaction of 1b (105 mg,
À40 °C, to which TMEDA (2 mL, 13.4 mmol) and CH3Li in Et2O
(1.14 M, 6.00 mL, 6.84 mmol) were added. The mixture was stirred
under Ar at À40 °C until the disappearance of 1b (monitoring the
visible spectrum in a solution: the shift of Qy peaks from 668 to
653 nm) and quenched with aq 2% HCl (10 mL) at À40 °C. The solu-
tion was diluted with CHCl3 and the separated organic phase was
washed with aq 4% NaHCO3 and H2O, dried over Na2SO4, and fil-
tered. After evaporation, the residue was dissolved in THF
(40 mL) and stirred with an excess amount of CH2N2 in Et2O at
room temperature for 15 min. All the solvents were distilled in va-
cuo and the residue was purified by alumina column chromatogra-
phy (CH2Cl2/hexane = 1:3) to give methyl carbinol 3 (32.0 mg,
197
À60 °C to room temperature gave phenyl carbinol 4 (8.4 mg,
13.4
mol, 7%) as a 1:4.5 mixture of (131S)- and (131R)-epimers:
lmol) with C6H5Li in Bu2O (1.9 M, 10 mL, 19 mmol) at
l
Vis (CH2Cl2) kmax = 653 (relative absorbance, 0.29), 598 (0.03),
502 (0.10), 402 nm (1.00); 1H NMR (400 MHz, CDCl3) d (131S/
R = 1/4.5) = 9.89 (1H, s, 5-H), 9.60 (1H, s, 10-H), 8.91 (1H, s,
20-H), 8.25 (1H, dd, J = 12, 18 Hz, 3-CH), 7.82/7.69 (2H, d,
J = 7.5 Hz, o-H of 131-Ph), 7.41/7.38 (2H, t, J = 7.5 Hz, m-H of
131-Ph), 7.38/7.32 (1H, t, J = 7.5 Hz, p-H of 131-Ph), 6.37 (1H, d,
J = 18 Hz, 31-CH trans to 3-C–H), 6.19 (1H, d, J = 12 Hz, 31-CH
cis to 3-C–H), 5.31/5.24 (1H, d, J = 16 Hz, 131-CH cis to 13-C–
Ph), 5.18/5.37 (1H, d, J = 16 Hz, 131-CH trans to 13-C–Ph), 4.64