Synthesis and SAR study of FD-891
T Itagaki et al
6
dried over Na2SO4, and concentrated under reduced pressure. The residue was The combined organic layers were dried over MgSO4, and concentrated under
purified by silica gel column chromatography (EtOAc/hexane = 1/10) to give
sulfone (62.7 mg, 97.8 μmol, 85%) as a colorless oil.
reduced pressure. The residue was purified by silica gel column chromato-
graphy (EtOAc/hexane =1/10) to give aldehyde (20.9 mg, 33.6 μmol, 91%) as a
colorless oil. The aldehyde was immediately used for the next step.
13: [α]22D +6.4 (c 0.72, CHCl3); IR (neat): 2929 cm− 1; 1H-NMR (400 MHz,
CDCl3) δ 7.73–7.70 (m, 2H), 7.63–7.57 (m, 3H), 3.89–3.76 (m, 4H), 3.26
(s, 3H), 3.19–3.16 (m, 1H), 2.40–2.31 (m, 1H), 2.21–2.12 (m, 1H), 1.78–1.70
(m, 1H), 1.68–1.61 (m, 1H), 1.12 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H),
0.93 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.110 (s, 3H), 0.107 (s, 3H),
0.095 (s, 3H), 0.08 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 153.5, 133.1, 131.4,
129.7, 125.0, 79.6, 72.0, 71.1, 56.2, 51.9, 43.9, 41.2, 27.2, 26.0, 25.9, 18.4, 18.1,
15.7, 12.5, 11.4, − 3.3, − 4.1, − 4.27, − 4.33; HR-MS (ESI) calcd. for
C30H57N4O5SSi2 [M++H] 641.3583, found 641.3568.
General procedure for the synthesis of FD-891 and its truncated
analogs: synthesis of FD-891 (1)
To a solution of sulfone 13 (30.1 mg, 46.9 μmol) and crude aldehyde (8.85 mg,
14.3 μmol) in DME (1.4 ml) was added KHMDS (94 μl, 0.5 M solution in
toluene, 46.9 μmol) at − 60 °C. After stirring for 20 min, the reaction mixture
was quenched with saturated NH4Cl aq. (3.0 ml) and extracted with EtOAc.
The combined organic layers were dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel column chromato-
graphy (EtOAc/hexane= 1/20) to give coupling adduct (8.11 mg, 7.83 μmol,
55%) as a colorless oil.
PT sulfone 14
[α]19 +1.2 (c 0.80, CHCl3); IR (neat): 2955 cm− 1 1H-NMR (600 MHz,
;
D
CDCl3) δ 7.72–7.70 (m, 2H), 7.64–7.58 (m, 3H), 3.94–3.93 (m, 1H), 3.85–3.76
(m, 3H), 3.28 (s, 3H), 3.19 (dd, J = 8.7, 8.7 Hz, 1H), 3.10 (dd, J = 9.0, 5.4 Hz,
1H), 2.36–2.30 (m, 1H), 2.16–2.10 (m, 1H), 1.79–1.73 (m, 1H), 1.73–1.67
(m, 1H), 0.98 (d, J = 7.2 Hz, 3H), 0.912 (s, 9H), 0.906 (s, 9H), 0.86
(d, J = 7.2 Hz, 3H), 0.11–0.08 (m, 12H); +++++13C-NMR (150 MHz, CDCl3)
δ 153.4, 133.1, 131.4, 129.7, 125.0, 76.4, 71.6, 70.9, 58.6, 51.7, 43.9, 35.5, 29.7,
27.1, 26.0, 25.9, 18.3, 18.1, 12.4, 11.7, − 3.8, − 4.1, − 4.4, − 4.6; LR-MS (EI) m/z
569 (M+-tBu), 117 (100%); HR-MS (EI) calcd. for C25H45N4O5SSi2 (M+-tBu)
569.2644, found 569.2669.
To a solution of coupling adduct (5.19 mg, 5.01 μmol) in MeCN (0.6 ml)
was added fluorosilic acid 40–45 wt% solution in water (0.100 ml) at room
temperature. After stirring for 4 h, the reaction mixture was quenched with
saturated NaHCO3 aq. (5.0 ml) and extracted with EtOAc. The combined
organic layers were dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
(EtOAc) to give FD-891 (1) (1.25 mg, 2.16 μmol, 43%) as a colorless oil.
1: [α]22D +4.9 (c 0.080, MeOH); IR (neat): 3446 (br), 1697 cm− 1; 1H-NMR
(600 MHz, CDCl3): δ 7.30 (s, 1H), 5.77 (ddd, J = 15.0, 10.2, 4.8 Hz, 1H),
5.63–5.49 (m, 4H), 4.84 (dt, J = 9.6, 3.6 Hz, 1H), 4.15 (brs, 1H), 4.00 (s, 1H),
3.86 (brs, 1H), 3.82 (dd, J = 9.6, 1.2 Hz, 1H), 3.62–3.58 (m, 2H), 3.34 (s, 3H),
3.25 (dd, J =4.8, 3.0 Hz, 1H), 3.16 (dd, J = 1.8, 1.8 Hz, 1H), 3.12 (ddd, J =11.4,
7.8, 3.6 Hz, 1H), 2.87 (brs, 1H), 2.56–2.45 (m, 3H), 2.33–2.17 (m, 4H), 2.09
(s, 3H), 2.03 (s, 3H), 2.01–1.94 (m, 2H), 1.91–1.81(m, 3H), 1.19 (d, J = 6.0 Hz,
3H), 1.14 (d, J = 7.8 Hz, 3H), 0.93 (d, J = 7.2 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H),
0.79 (d, J = 7.8 Hz, 3H); 13C-NMR (150 MHz, CDCl3): δ 168.8, 144.0, 141.7,
PT sulfone 15
[α]18 − 0.30 (c 0.31, CHCl3); IR (neat): 2928 cm− 1 1H-NMR (600 MHz,
;
D
CDCl3) δ 7.70 (dd, J = 8.4, 1.8 Hz, 2H), 7.62–7.59 (m, 3H), 3.88 (m, 1H),
3.87–3.84 (m, 1H), 3.82–3.80 (m, 2H), 3.44 (dd, J = 9.6, 8.2 Hz, 1H), 3.37 (dd,
J = 9.6, 6.6 Hz, 1H), 2.31–2.25 (m, 1H), 2.18–2.12 (m, 1H), 1.73–1.68 (m, 2H),
0.94 (d, J = 7.2 Hz, 3H), 0.903 (s, 9H), 0.899 (s, 9H), 0.87 (s, 9H), 0.84 (d,
J = 6.6 Hz, 3H), 0.11–0.09 (m, 12H), 0.02–0.01 (m, 6H); 13C-NMR (150 MHz,
CDCl3) δ 153.5, 131.4, 129.7, 125.0, 71.6, 70.9, 66.6, 51.8, 43.5, 38.3, 29.7, 27.4, 135.8, 130.2, 129.4, 129.3, 128.1, 124.7, 82.7, 78.4, 76.5, 73.2, 71.0, 70.9, 56.0,
26.02, 25.96, 25.9, 18.4, 18.1, 12.3, 11.3, − 3.6, − 4.1, − 4.3, − 4.4, − 5.3, − 5.4;
LR-MS (EI) m/z 669 (M+-tBu), 117 (100%); HR-MS (EI) calcd. for
C30H57N4O5SSi3 (M+-tBu) 669.3352, found 669.3357.
55.9, 55.0, 39.7, 39.6, 38.2, 36.8, 36.0, 35.9, 34.5, 34.4, 16.5, 16.4, 16.3, 15.6,
13.7, 11.6, 4.9; HR-MS (ESI) calcd. for C33H55O8 [M++H] 579.3891, found
579.3878.
PT sulfone 16
Truncated analog 7
[α]24 − 7.5 (c 0.72, CHCl3); IR (neat): 2954 cm-1; 1H-NMR (400 MHz,
[α]28 − 26 (c 0.080, CHCl3); IR (neat): 3421 (br), 1696 cm− 1 1H-NMR
;
D
D
CDCl3) δ 7.72–7.70 (m, 2H), 7.65–7.57 (m, 3H), 3.93–3.89 (m, 1H), 3.83 (dd,
J = 9.6, 7.2 Hz, 2H), 3.76–3.71 (m, 2H), 3.64 (dt, J = 9.6, 7.2 Hz, 1H), 2.21–2.15
(m, 2H), 1.74–1.69 (m, 1H), 1.65–1.57 (m, 1H), 1.51–1.43 (m, 1H), 0.95
(d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.11 (s, 3H), 0.10
(m, 6H), 0.08 (s, 3H), 0.04 (s, 6H); 13C-NMR (100 MHz, CDCl3) δ 153.5,
133.1, 131.4, 129.7, 125.0, 71.6, 69.2, 60.3, 51.7, 43.4, 35.3, 26.9, 26.0, 25.9,
25.8, 18.3, 18.1, 18.0, 11.0, − 4.18, − 4.22, − 4.5, − 4.6, − 5.3; HR-MS (ESI)
calcd. for C33H65N4O5SSi3 (M++H) 713.3978, found 713.3974.
(400 MHz, CDCl3): δ 7.30 (s, 1H), 5.76 (ddd, J =15.2, 9.6, 5.2 Hz, 1H),
5.62–5.48 (m, 4H), 4.84 (dt, J = 9.2, 3.6 Hz, 1H), 4.15 (brs, 1H), 3.88
(d, J = 8.8 Hz, 1H), 3.82 (dd, J = 9.6, 2.0 Hz, 1H), 3.60 (brs, 1H), 3.47
(d, J = 4.8 Hz, 2H), 3.37–3.35 (m, 4H), 3.25 (dd, J = 4.8, 2.4 Hz, 1H), 3.15
(dd, J = 2.0, 2.0 Hz, 1H), 3.14–3.10 (m, 1H), 2.72 (brs, 1H), 2.56–2.28 (m, 3H),
2.27–2.17 (m, 4H), 2.09 (s, 3H), 2.02 (s, 3H), 1.99–1.82 (m, 6H), 1.14
(d, J = 7.2 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 0.91 (d, J =6.4 Hz, 3H), 0.83
(d, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 168.8, 144.0, 141.7, 135.8,
130.0, 129.9, 129.2, 128.1, 124.6, 78.2, 76.4, 76.0, 73.4, 71.0, 70.9, 59.2, 55.9,
55.1, 39.3, 38.2, 36.6, 36.1, 35.9, 35.2, 34.54, 34.47, 16.5, 16.3, 15.6, 13.7, 11.7,
9.7; HR-MS (ESI) calcd. for C32H53O8 [M++H] 565.3735, found 565.3724.
PT sulfone 17
[α]27 +3.40 (c 1.22, CHCl3); IR (neat): 2929 cm− 1 1H-NMR (400 MHz,
;
D
CDCl3): δ 7.71–7.69 (m, 2H), 7.63–7.57 (m, 3H), 3.91 (q, J =5.4 Hz, 1H), 3.83
(ddd, J = 14.6, 11.2, 5.9 Hz, 1H), 3.74 (ddd, J = 14.1, 10.7, 5.4 Hz, 1H),
3.56–3.49 (m, 2H), 2.20–2.07 (m, 2H), 1.72–1.66 (m, 1H), 0.91–0.87
(m, 21H), 0.08 (s, 3H), 0.07 (s, 3H), 0.03 (s, 6H); 13C-NMR (100 MHz,
CDCl3): δ 153.5, 133.1, 131.4, 129.7, 125.0, 71.1, 64.3, 53.1, 40.6, 26.6, 25.9,
25.8, 18.2, 18.1, 12.2, − 4.4, − 4.6, − 5.4, − 5.5; LR-MS (FAB) m/z 555.3
(M++H), 73.1 (100%); HR-MS (FAB) calcd. for C25H47N4O4SSi2 (M++H)
555.2851, found 555.2859.
Truncated analog 8
[α]28 − 21 (c 0.23, CHCl3); IR (neat): 3407 (br), 1680 cm− 1 1H-NMR
;
D
(400 MHz, CDCl3): δ 7.30 (s, 1H), 5.76 (ddd, J =15.2, 9.6, 5.2 Hz, 1H),
5.63–5.48 (m, 4H), 4.85 (dt, J =9.2, 3.6 Hz, 1H), 4.15 (brs, 1H), 3.91–3.88
(m, 2H), 3.79 (dd, J = 10.8, 4.0 Hz, 1H), 3.71 (dd, J = 10.8, 5.6 Hz, 1H), 3.65–
3.60 (m, 2H), 3.24 (dd, J = 4.8, 2.8 Hz, 1H), 3.15 (dd, J = 2.0, 2.0 Hz, 1H),
3.13–3.10 (m, 1H), 2.56–2.43 (m, 4H), 2.33–2.17 (m, 5H), 2.08 (s, 3H), 2.02
(s, 3H), 2.00–1.90 (m, 5H), 1.80–1.74 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H), 0.99
(d, J = 7.2 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H), 0.83 (d, J = 7.2 Hz, 3H); 13C-NMR
(100 MHz, CDCl3): δ 168.9, 144.2, 141.7, 135.8, 130.9, 129.4, 129.1, 128.3,
124.5, 76.2, 76.1, 73.7, 71.0, 70.9, 67.9, 55.9, 55.1, 39.1, 38.2, 36.4, 36.1, 35.9,
34.6, 34.5, 16.5, 16.3, 15.6, 13.6, 11.8, 9.1; HR-MS (ESI) calcd. for C31H51O8
Synthesis of aldehyde 12
To a solution of precursor alcohol (23.0 mg, 37.0 μmol), AZADO (0.56 mg,
3.7 μmol), bpy (0.58 mg, 3.7 μmol) and DMAP (0.90 mg, 7.40 μmol) in MeCN
(1.90 ml) was added CuCl (0.73 mg, 7.4 μmol) at room temperature. After
stirring for 15 min under an O2 atmosphere, the reaction mixture was
quenched with saturated NaHCO3 aq. (5.0 ml) and extracted with EtOAc. [M++H] 551.3578, found 551.3569.
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