Dichlorolissoclimide 3 [IC50 1 ng/ml (P388); 14 ng/ml (human
KB)] has a very unusual structure containing a trans-diequatorial dichloride
and a succinimide unit. One of the key steps towards the total synthesis
of 3 is the thermal rearrangement of the diaxial dichloride, giving the
diequatorial dichloride 1. Functionalization of the B-ring of 1 provides
2, onto which we will construct the succinimide unit and the terminal alkene.
(a) MeOH, KOH, pyrrolidine, 77%; (b) NaBH4, EtOH, 100%; (c) i) Li, NH3;
ii) MeI, THF, reflux, 61%; (d) MOMCl, PhN(CH3)2, CH2Cl2, 15°C, 76%;
(e) i) TsNHNH2, MeOH; ii) NaH, toluene, reflux, 79%; (f) SO2Cl2, CH2Cl2,
100%; (g) H3O+, 100%; (h) PCC, CH2Cl2, 90% (9:1 = 82:18); (i) sealed tube,
neat, 195±2°C, 60h, 92%.
So far we have synthesized the aldehyde (18) (Scheme 3).
(a) PhN(CH3)3+Br3-, THF, 0°C ® rt., 12h, 91%; (b) DBU, toluene,
reflux, 12h, 94%; (c) allylmagnesiumbromide, THF,
-78°C ® rt., 2h, 90%; (d) PCC, molecular sieves 4Å, CH2Cl2,
rt., 24h, 84%; (e) NaBH4, CeCl3, EtOH, 0°C ® rt., 85%;
(f) i) NaH, THF, 0°C, 20min; ii) PMBCl, 10mol% TBAI, THF, rt., 90%;
(g) 1mol% OsO4, 1.1eq. NMO, acetone/H2O=5:1, 0°C, 24h, 60%; (h) 2-methoxypropene,
PPTS, rt., 20min; (i) i) B2H6, THF, 0°C, 8h; ii) 10% NaOH, H2O2, 0°C,
2h; (j) TBSCl, Im, DMF/CH2Cl2=1:1; (k) i) acidic cleavage; ii) NaIO4, MeOH/H2O=1:1.
(a) 2,5-hexadienyl-B(Ipc)2, Et2O; (b) PMBCl, 10mol% TBAI, THF, rt.; (c)
i) O3, py, CH2Cl2; ii) Jones; (d) i) SOCl2;
ii) NH3; (e) TBAF, THF, 0°C; (f) PCC, CH2Cl2; (g) Wittig; (h) CAN.