. sman, CEM 20 //2007 Total ynthesis of Rapamycin Matthew L. Maddess, Miles. Tackett, idenori Watanabe, Paul E. ennan, Christopher D. pilling, James. cott, David P. sborn, and teven V. Ley* Angew. Chem. Int. Ed. 2007, 6, 59 597 Presented by: ami sman Jan. nd 2007. Introduction Me (-)-rapamycin () 9 Me Me First isolated in 975 from treptomyces hygroscopicus found in Easter Island soil Recognized for its potent immunosuppressive action Blocks entry of resting immune cells into the cell cycle Blocks progression of cells in the early phase of the cell cycle, causing cell cycle arrest Mammalian target for rapamycin is serine/threonine protein kinase Involved in intracellular events such as proliferation, growth, differentiation, migration, and survival. -chreiber,. L. Cell 992, 70, 365-368 - chreiber,. L. et. al. Angew. Chem., In. Ed. Eng. 992, 3, -00
. sman, CEM 20 //2007 Previous yntheses Me (-)-rapamycin () 9 Me Me previous total syntheses First synthesis of naturally occurring enantiomer was by the icolaou group Then came the chreiber group with their synthesis, using the Evans-Tischenko reaction, and later in the synthesis the Mukaiyama macrocyclization. The Danishefsky group completed their synthesis, highlighting at the end of the synthesis the aldol reaction via Ti enolate, to the macrocycle structure. Finally the mith group came with their synthesis longest linear sequence from first point convergence of steps first synthesis of Demethoxy-rapamycin convergent approach permitted straight forward preparation of analogs. -K.C. icolaou et. al., JAC 993,, 5, 9 -. L. chreiber et. al., JAC 993, 5, 7906 -. J. Danishefsky et. al., JAC 993, 5, 935 -A. B. mith et. al. JAC 995, 7, 507 Retrosynthetic Analysis Me (-)-rapamycin () 9 Me Me TB PMB R 2 PMB Me C-C electrophile 5 Me TB Me 20 C-C20 lactone 3 I R C2-C stannane 2 TE C-C bromide Me 33 C33-C epoxide 6 Me 3 n 2
. sman, CEM 20 //2007 ynthesis of C-C bromide Me 9 Me Me 7 Tr. (CCl) 2, DM DIPEA, C 2 Cl 2 2. (C 2 ) 3, BF 3.Et 2, C 2 Cl 2, -78 o C - RT, 99% over two steps. LiBEt 3, TF, 0 o C, 99% Kinetic bromoalkene, only isomer dedected. 3.Py, DM, DIPEA, C 2 Cl 2, 0 o C 2. KMD, [8]crown-6, C 2 Me (CF 3 C 2 ) 2 P()C 2 C 2 Me, 2,TF, 96% over two steps. 8 9. MsCl, Et 3, DMAP, C 2 Cl 2, then Li, DMF, 70%. DIBAL-, C 2 Cl 2, -5 o C, 99% ynthesis of C-C Electrophile 5 2. Lipase P-30 (8wt%), DME/ vinyl acetate (5:), r.t., h, 75%, 96-99%ee. TBCl, Im, C 2Cl 2 2. K 2C 3, Me 3. a, PMPCl, TBAI, TF. TBAF, TF, 90% over four steps. R 3 R=Ac R=PMB. 3.Py, DM, DIPEA, C 2 Cl 2, 0 o C, 99% for both 3 &. 5 R=Ac R=PMB R. sbuli, allylmethyl ether, TF, -78 o C, then (-)-(Me)BIpc 2, then BF 3.Et 2, then 5, h, then 3 a, 30% 2 2, -78 o C - RT 2. K 2C 3, Me, r.t., 0% over two steps Me 9 Me Me PMB PMB. s, M, acetone/ water, r.t., 78% PMB PMB. a, PMBCl, TBAI, DMF, r.t,99% Me 9 Me 8 Me 7. Pb(Ac), Ph, 99% PMB PMB Me 5a own alkoxyallylation (5 to 7) selectivity was confirmed by X-ray analysis Direct ozonolysis of 8 was problematic. 3
. sman, CEM 20 //2007 ynthesis of C-C Electrophile 5 R Me R R. LiMD, TF, -78 + o C, then Ac, 82% for 5, 92% for Me R 2Me 5 R=Ac R=PMB Me R=Ac 23 R=PMB. PMB-TCA, TrBF (5mol%), TF, r.t., 7% Me 9 Me Me PMB Me 5b PMB. CA, Me, r.t., 80% 2. Ag 2, MeI, C 2Cl 2, 50 o C, 7% 3. LiMD, Me(Me). Cl, TF, -20 o C-- o C, 97% PMB PMB 2 Me Me econd approach for electrophile 5 using the groups recently developed butane-2,3-diacetal (BDA, 2). BDA allowed for a highly selective aldol condensation with 5 or. ynthesis of C-C Fragment TEPMB 26 Me. tbuli, TF, -96 o C, then 5a, -96 o C to -78 o C, 66% PMB. 3.Py, DM, DIPEA, C 2Cl 2, 0 o C, 99% 2. Zn(B ) 2, Et 2, -20 o C, 3days, 80% 3. TETf, 2,6-lutidine, C 2Cl 2, -78 o C, 0min, 99% + Me PMB Me PMB PMB 25a 25a/25b 3: PMB 25b Me 9 Me Me. tbuli, TF, -96 o C, then 5b, -96 o C to -78 o C, 80% Me PMB 27 PMB. Zn(B ) 2, Et 2, -20 o C, 2h, 83% 2. TECl, Im, DMF, 50 o C, 93% TEPMB Zn(B ) 2 afforded correct stereochemistry Addition of and Weinreb amide 5b offered higher yields to give 27 without any diastereomeric mixtures. Control D 2 studies indicated C-C vinyl bromide cleanly transmetalated, without abstraction of from C dithiane. Me PMB
. sman, CEM 20 //2007 TB Me ynthesis of C-C Fragment Me TEPMB 26 PMB TB Me. 6, tbuli, TF/MPA(5:), -78 o C to -0 o C, 77%. TF/Me/ 2 (:9:), PhI(CCF 3) 2, r.t., 8% 2. 30, DCC, DMAP, C 2Cl 2, -5 o C, 2h, 8% 3. DDQ, p 7 buffer, C 2Cl 2, r.t., 93%. (CCl) 2, DM, Et 3, C 2Cl 2, 99% Me PMB TE PMB Me 9 Me Me 3 Me C TE TB Me 6 C 2 30 TB Me ynthesis of C-C Fragment Me TEPMB PMB TB Me. 6, tbuli, TF/MPA(5:), -78 o C to -0 o C, 8%. TF/Me/ 2 (:9:), PhI(CCF 3) 2, r.t., 83% 2. 30, DCC, DMAP, C 2Cl 2, -5 o C, 2h, 99% 3. DDQ, p 7 buffer, C 2Cl 2, r.t., 90%. (CCl) 2, DM, Et 3, C 2Cl 2, 99% Me PMB TE PMB Me 9 Me Me 3 Me C TE TB Me 6 C 2 30 5
. sman, CEM 20 //2007 Final tage of ynthesis TB TB Me. CrCl 2, CI 3, TF, 0 o Me C to RT, 82% 2. [Pd(PFur 3) 2Cl 2], (Me 3n) 2, MP, dark, RT, 68% Me 3 Me C TE 2a Me Me 3n TE 9 Me Me TB Me Me Alloc Me 0 TE. LiAl(tBu) 3, TF, - o C, 8% 2. Alloc-Cl, -pyrrolidinopyridine, C 2Cl 2, 8%. [Pd(PFur 3) 2Cl 2], 3, MP, dark, RT, 69% TB Me Me Me TE o minor geometric isomer was detected of the tille coupling Possibly Z isomer of 3 equilibrated with the E, or Z isomer react slower than E isomer Me I 3 (E/Z 6:) Final tage of ynthesis 0. 0.M Li in 2,TF, 0 o C, 89% 2. TETf, 2,6-lut, C 2Cl 2, -20 o C to RT, 88% 3. C 2C 2, 2,6-lut, C 2Cl 2, -20 o C, 66% TB Me Me Alloc Me Me 2C TE 9 Me Me TB. LiMD, TF, -78 o C to -20 o C, 78% 2. [Pd(PPh 3) ], dimedone, TF, RT, 80% TB TE. catechol, DCC, DMAP, C 2Cl 2, 0 o C to RT, 88% 2. K 2C 3, DMF, RT, 8% Me Me Me TE Me 3 TE Alloc Me Me TE TE equence of events from 0 to is crucial to avoid epimerization of C Methy group. 6
. sman, CEM 20 //2007 Final tage of ynthesis TB Me Me TE Me. PhI(Ac) 2, C 3 C/ 2 (:), 0 o C 2. DMP, Py, C 2Cl 2, RT, 6% over two steps TE TB Me Me TE Me TE 3. F.Py, TF, 50 o C, 6% Me 9 Me Me (-)-rapamycin ummary ew and efficient convergent route to the synthesis of (-)-Rapamycin Used their recently developed butane-2,3-diacetal chemistry as protecting and stereodirecting functionality for the aldol reaction Efficient macroetherification/catechol strategy for the formation of the macrocyclic core of rapamycin. 7