Electronic upplementary Material (EI) for Natural Product eports. This journal is The oyal ociety of Chemistry 2017 upporting Information The synthesis of cardenolide and bufadienolide aglycones, and related steroids bearing a heterocyclic subunit Michał Michalak, Karol Michalak and Jerzy Wicha Institute of rganic Chemistry, Polish Academy of ciences Kasprzaka 44/52, 01-224 Warsaw, Poland jerzy.wicha@icho.edu.pl Table of contents Graphical presentation of preferred reagent approaches to C14 and C16 double bonds in steroid ring D...2 uzicka s synthesis of allo-uzarigenin...2 ondheimer s synthesis of digitoxigenin via the 14β-hydroxy etiocholanic acid derivative 8...3 ondheimer s synthesis of resibufogenin and bufalin...3 Deghenghi s synthesis of periplogenin (19-desoxostrophanthidin)...4 Wiesner s synthesis of digitoxin...4 Daniewski et al. total synthesis of 9(11)-dehydrodigitoxygenin from Wieland-Miescher dione (384) applying vinyliodide 31 hydrogenation with diimide and tork s radical cyanation...5 tork s total synthesis of (+)-digitoxigenin. Part 1. The construction of tricyclic ABC intermediate applying intramolecular Diels-Alder reaction...6 tork s total synthesis of (+)-digitoxigenin. Part 2. Building up ring D and construction of the lactone moiety...6 verman s total-synthetic approach to C19-functionalized cardenolides. Part 1. etrosynthetic plan...7 verman s total-synthetic approach to cardenolides. Part 2. The synthesis of the ring A building block 55...7 cheme 12. verman s synthetic approach to cardenolides. The synthesis of the CD building block 63 and the androstane derivative 69...8 eferences...8 1
cheme 1. Graphical presentation of preferred reagent approaches to C14 and C16 double bonds in steroid ring D. C 3 peroxyacid C 3 C 3 peroxyacid C 3 C 3 C 3 C 3 TM 2 /cat. 2 /cat. 2 /cat. C 3 C 3 C 3 TM cheme 2. uzicka s synthesis of allo-uzarigenin. 1-3 Ac 4 Ac Ac 1. Zn, BrC 2 C 2 benzene/et 2, 15 min. 2. Ac 2, Py 73% 1. NB, Py, reflux, 0.5h 2. Py, 0.5h 3. Ac 2, Py 12% 35% 67% 1 2 3 2 Pd/Ba 4 60% 1. Br 2, cat. Br Ac/CCl 4 2. Py, reflux 5 Ac Ac 6 Cl, Me, rt Ac monoperoxyphthalic a. CCl 3, rt allo-uzarigenin (7) 2
cheme 3. ondheimer s synthesis of digitoxigenin 4-5 via the 14β-hydroxy etiocholanic acid derivative 6-8 8. 9 steps C 2 Me 1. K 2 C 3, Me 2. Ac 2 2. MeLi, TF Li Et TF Ac ca. 45% Ac 28 8 140 Et 1. 2% 2 4 Me 2. Ac 2, Py C 2 Et 1. e 2, benzene reflux 2. 5% Cl, Me 141 45% 142 24% digitoxigenin cheme 4. ondheimer s synthesis of resibufogenin and bufalin. 9 1. Li 2. 2N 2 4 3. K 2 C 3 Me Et C 2 1.Li/N 3-70 to -50 C 2. C 2 N 2 3. Ac 2, Py C 2 Me 74% 95% Ac 9 10 11 Ac 1.PCl 3 chrom. 2. K 2 C 3 Me 54% (Me) 2 C PCl 3 DMF 79% C 2 1. CDI 2. (t-bu) 3 Al 3. 2 4 t-bu 91% 12 204 Me C 1. 2 4 Me 2. Ac 2, Py Ac Ac 205 206 207 C 1. Na aq Et 2. BrC 2 C 2 Me Zn, DMF, 70 C 3. chrom. 15% 90% 1. Cl, aq Me and then p-tscl, Py 2. DMF, 80 C 3. Al 2 3 4. Ac 2, Py 1. NB 2. Al 2 3 LiAl 4 Et 2-65 C Ac CDI - N,N'-carbonyldiimidazole 220 resibufogenin (19) bufalin (14) 3
cheme 5. Deghenghi s synthesis 10-11 of periplogenin (19-desoxostrophanthidin). Ac Ac 1. LiAl 4 1. NB TF Ac aq dioxane 2. Ac 2 2. K Py Me anhyd Cu 4 acetone Ac 13 14 15 1. LiAl 4 TF, reflux 2. Ac 2, Py 1. 0.05 N 2 4 Me 2. Ac 2, Py dioxane Ac 2 Cr 4 DMF Ac 16 17 18 Ac Li Et Et 1N Cl benzene, Et 2 Me Ac Ac 19 20 Periplogenin (21) cheme 6. Wiesner s synthesis of digitoxin. 12-14 11 steps Et 2 Li 1. Ac 2, Py 2. acetone aq. CaC 3, reflux 3. 2, Pd/CaC 3 Et 93% Bn 28 229 22 1. m-cpba CCl 3, Ac AcNa 2. NaB 4 DCM-water MsCl, Py 1. NB aq acetone- Ac 2. a-ni DCM, Me AcK Ac 87% 85% 78% 23 24 25 26 2, Pd/C Etbenzene 93% digitoxigenin (27) stereoselective -glycosylation = tridigitoxoside unit digitoxin (1) 4
cheme 7. Daniewski et al. 15-17 total synthesis of 9(11)-dehydrodigitoxygenin from Wieland- Miescher dione (384) applying vinyliodide 31 hydrogenation with diimide and tork s radical cyanation. 18 5 steps 1. MeNa Me 2, Pd/C 2. 2, Pd/rC 3 Py 384 28 40% 29 87% 1. K-electride 2. N 2 4 2 3. I 2, Et 3 N I N 2 4 2 PrC 2 air I t-bu-nc Bu 3 ncl AIBN NaB 3 () t-bu 46% 30 31 32 33 1. DP PPT 2. MeLi benzene 50% TP DP - dihydropyrane PPT - pyridinium p-toluenesulfonate MoP -oxodiperoxymolibdenum(pyridine) 34, = 35, = 1. LDA, TF 2. MoP MPA-TF 50% 86% Ph 3 P=C=C= Et 3 N, benzene 52% TP 36 82% 5
cheme 8. tork s 19 total synthesis of (+)-digitoxigenin. Part 1. The construction of tricyclic ABC intermediate applying intramolecular Diels-Alder reaction. 1. 3 DCM-Me TM TMCl, Et 3 N 2. NaB 4, Me C DMF 3. NaI 4 C 54% 37 38 39 1. Ph 2 P NaB(Ac) 3 benzene 67% C C 2 n-buli TF-MPA 2. wern ox. 42 Et 2 P n-buli, TF C 60% 40 41 43 toluene 200 o C 75% in 2 steps 44 1. Cl aq TF-acetone 2. NaB 4 -CeCl 3 7 2 Et 64% 45 1. DEAD, TFA Ph 3 P, BzNa TF 2. (Me 3 )BF 4 60% CF 3 C 2 46 DEAD - diethyl azodicarboxylate cheme 9. tork s total synthesis of (+)-digitoxigenin. Part 2. Building up ring D and construction of the lactone moiety. 46 1. EtNa, Et 2. TBCl im, DMF 78% 1. C 6 5 C 3 NaC 3 2. BF 3 Et 2-78 C to rt 63% TB TB TB 1. BrMg TF, rt 2. TBAF C 67% TM TB 1. N 2 Cl AcNa, Et 2. CDI, DCM, rt Bu 3 n AIBN, benzene then silica gel 40% 95% TB 51 99 47 1. BnC 2 Li TF, -78 C 2. Pd/C, Et 85% 48 49 TB 101, 17 :17 >4:1 102 digitoxigenin (27) 1. Ph 3 P=C=C= Et 3 N, benzene 2. Ts, Me 72% TB 1. LiNEt 2, TF, 0 C 2. BT 3. chromat. 50 73% AIBN - 2,2'-azobis(2-methylpropionitrile) CDI - N,N'-carbonyldiimidazole BT - 2,6-di-tert-butyl-4-methylphenol 6
cheme 10. verman s total-synthetic approach to C19-functionalized cardenolides. 20-23 Part 1. etrosynthetic plan. 2 3 19 11 17 13 1 9 14 10 8 5 52 Tf 53 + I 54 55 8 7 56 = C 2 P or, P = protective group cheme 11. verman s total-synthetic approach to cardenolides. Part 2. The synthesis of the ring A building block 55. Ph Ph N B 58 B 3 Me DCM, -25 C 98%, 93%ee Ac 2, Et 3 N DMAP 96% 57 Ac 60 1. KMD TBDMCl MPA 2. KF, K 2 C 3 MeI, DMF I 2, PPh 3, im toluene 59 LiAl 4 C 2 Me 61 62 97% in 2 steps 55 I 7
cheme 12. verman s synthetic approach to cardenolides. The synthesis of the CD building block 63 and the androstane derivative 69. 1. NaB 4 2. Me 2 NN 2 Ac, Et 3. TM-im TM 1. Et 2 NLi TF, MPA, -78 C then 55 2. Ac, AcNa aq TF 1. MsCl, py 2. K, 18-C-6 DM 85% N 337 NMe 2 63 90% 64 1. NaB 4 CeCl 3 7 2 1. mi 2, TF Me TM-im 2. V(acac) 2 t-bu 2 3. TPAP, NM 68% ad then 2 2. TBAF silica gel, CCl 3 8 KMD PhNTf 2-78 C, TF 65 66 67 Tf Pd(dppb) AcK, DMA 75 C 90% 68 69 Pd(dppb) - palladium bis(diphenylphosphino)butane eferences: 1. P. A. Plattner, L. uzicka,. eusser and E. Angliker, elv. Chim. Acta, 1947, 30, 1073-1079. 2. P. A. Plattner,. eusser and E. Angliker, elv. Chim. Acta, 1946, 29, 468-473. 3. P. A. Plattner, L. uzicka,. eusser and E. Angliker, elv. Chim. Acta, 1947, 30, 395-402. 4. N. Danieli, Y. Mazur and F. ondheimer, J. Am. Chem. oc., 1962, 84, 875-876. 5. F. ondheimer, Chem. Br., 1965, 454-464. 6. L. uzicka, P. A. Plattner,. eusser and J. Pataki, elv. Chim. Acta, 1946, 29, 936-941. 7. P. A. Plattner, L. uzicka,. eusser, J. Pataki and K. Meier, elv. Chim. Acta, 1946, 29, 942-949. 8. L. uzicka, P. A. Plattner,. eusser and K. Meier, elv. Chim. Acta, 1947, 30, 1342-1349. 9. F. ondheimer, W. McCrae and W. G. almond, J. Am. Chem. oc., 1969, 91, 1228-1230. 10.. Deghenghi, A. Philipp and. Gaudry, Tetrahedron Lett., 1963, 4, 2045-2048. 11.. Deghenghi, Pure Appl. Chem., 1970, 21, 153-166. 12. T. Y.. Tsai, A. Minta and K. Wiesner, eterocycles, 1979, 12, 1397-1401. 13. K. Wiesner and T. Tsai, Pure Appl. Chem., 1986, 58, 799-810. 8
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